Potentiators Of Glutamate Receptors

ABSTRACT

This application relates to a substituted hydroxyphenyl ketone compound of formula I, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and its use in treating migraine. 
     
       
         
         
             
             
         
       
     
     This application also relates to processes for preparing a compound of formula I, and intermediate compounds useful therein.

This application is a division of U.S. patent application Ser. No.11/718,753 filed Nov. 15, 2005.

The present invention provides a compound of formula I, pharmaceuticalcompositions thereof, and methods of using the same, as well asprocesses for preparing the same, and intermediates thereof.

BACKGROUND OF THE INVENTION

The excitatory amino acid L-glutamate (at times referred to hereinsimply as glutamate) through its many receptors mediates most of theexcitatory neurotransmission within the mammalian central nervous system(CNS) and has been implicated in numerous peripheral nervous system(PNS) pathways. The excitatory amino acids, including glutamate, are ofgreat physiological importance, playing a role in a variety ofneurological, physiological and psychiatric processes, such as synapticplasticity, motor control, respiration, cardiovascular regulation,sensory perception, and emotional responses.

Glutamate acts via at least two distinct classes of receptors. One classis composed of the ionotropic glutamate (iGlu) receptors that act asligand-gated ion channels. Via activation of the iGlu receptors,glutamate is thought to regulate fast neuronal transmission within thesynapse of two connecting neurons in the CNS. The second general type ofreceptor is the G-protein or second messenger-linked “metabotropic”glutamate (mGlu) receptor. Both types of receptors appear not only tomediate normal synaptic transmission along excitatory pathways, but alsoparticipate in the modification of synaptic connections duringdevelopment and throughout life. Schoepp, Bockaert, and Sladeczek,Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, BrainResearch Reviews, 15, 41 (1990).

The mGlu receptors belong to the Class C G-protein coupled receptor(GPCR) family. This family of GPCR's, including the calcium-sensingreceptors, GABA_(B) receptors and sensory receptors, are unique in thateffectors bind to the amino-terminus portion of the receptor proteintranslating a signal via the transmembrane segments to the intracellularmatrix through receptor/G-protein interactions. Ozawa, Kamiya andTsuzuski, Prog. Neurobio., 54, 581 (1998). It has been demonstrated thatthe receptors are localized either pre- and/or post-synapticly wherethey can regulate neurotransmitter release, either glutamate or otherneurotransmitters, or modulate the post-synaptic response ofneurotransmitters, respectively.

At present, there are eight mGlu receptors that have been positivelyidentified, cloned, and their sequences reported. These are furthersubdivided based on their amino acid sequence homology, their ability toeffect certain signal transduction mechanisms, and their knownpharmacological properties. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio.,54, 581 (1998). For instance, the Group I mGlu receptors, which includethe mGlu1 and mGlu5, are known to activate phospholipase C (PLC) viaGαq-proteins thereby resulting in the increased hydrolysis ofphosphoinositides and intracellular calcium mobilization. There areseveral compounds that are reported to activate the Group I mGlureceptors including DHPG, (+/−)-3,5-dihydroxyphenylglycine. Schoepp,Goldworthy, Johnson, Salhoff and Baker, J. Neurochem., 63, 769 (1994);Ito, et al., Neurorep., 3, 1013 (1992). The Group II mGlu receptorsconsist of the two distinct receptors, mGlu2 and mGlu3 receptors. Bothreceptors are negatively coupled to adenylate cyclase via activation ofGαi-protein. These receptors can be activated by a group-selectivecompound such as(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate. Monn, etal., J. Med. Chem., 40, 528 (1997); Schoepp, et al., Neuropharmacol.,36, 1 (1997). Similarly, the Group III mGlu receptors, including mGlu4,mGlu6, mGlu7 and mGlu8, are negatively coupled to adenylate cyclase viaGαi and are potently activated by L-AP4(L-(+)-2-amino-4-phosphonobutyric acid). Schoepp, Neurochem. Int., 24,439 (1994).

It should be noted that many of the available pharmacological tools arenot ideal in that they cross react not only on the receptors within agroup of mGlu receptors but also often have some activity between groupsof mGlu receptors. For instance, compounds such as 1S,3R-ACPD,(1S,3R)-1-aminocyclopentane-trans-1,3-dicarboxylic acid, are believed toactivate all of the Group I, II and III mGlu receptors depending uponthe dose utilized while others, such as 1S,3S-ACPD,(1S,3S)-1-aminocyclopentane-trans-1,3-dicarboxylic acid, are moreselective for the Group II receptors (mGlu2/3) than the Group I(mGlu1/5) or Group III (mGlu4/6/7/8). Schoepp, Neurochem. Int., 24, 439(1994). To date, there are very few examples of selective agents for themGlu receptors. Schoepp, Jane, and Monn, Neuropharmacol., 38, 1431(1999).

It has become increasingly clear that there is a link between modulationof excitatory amino acid receptors, including the glutamatergic system,through changes in glutamate release or alteration in postsynapticreceptor activation, and a variety of neurological, psychiatric andneuroinflammatory disorders. e.g. Monaghan, Bridges and Cotman, Ann.Rev. Pharmacol. Toxicol., 29, 365-402 (1989); Schoepp and Sacann,Neurobio. Aging, 15, 261-263 (1994); Meldrum and Garthwaite, Tr.Pharmacol. Sci., 11, 379-387 (1990). The medical consequences of suchglutamate dysfunction make the abatement of these neurological processesan important therapeutic goal.

Leukotrienes are potent local mediators, playing a major role ininflammatory and allergic responses including arthritis, asthma,psoriasis, and thrombotic disease. Leukotrienes are straight chaineicosanoids produced by the oxidation of arachidonic acid bylipoxygenases in several cell types including: eosinophils, neutrophils,mast cells, leukocytes, and macrophages. At the present time, there aretwo established Class A GPCR receptors for the cysteinyl-leukotrienes(CysLT1 and CysLT2) which the leukotrienes LTC4, LTD4 and LTE4 activate,mediating their proinflammatory effects. Each of the CysLT receptors hasdistinct tissue distributions and associations with physiologicalresponses. Also, the leukotriene LTD4 has a higher affinity for theCysLT1 receptor than the other leukotrienes. Back, M. Life Sciences 71,611-622, (2002). The leukotrienes, especially LTD4 and its receptorCysLT 1, have been implicated in the pathogenesis of airway and allergicdiseases such as asthma by contributing to bronchoconstriction, mucussecretion, and eosinophil migration. Thus, leukotrienes have been shownto play an important role in the pathology of asthma. Rigorous proof forthe role of leukotrienes in asthma has been provided by several pivotalclinical trials in which orally administered LTD4 receptor antagonistsproduce clear therapeutic benefit in asthma patients. These benefitsinclude reduction in the use of classic asthma therapies such ascorticosteroids. Kemp, J. P., Amer. J. Resp. Medi. 2, 139-156, (2003).

Numerous investigations confirm the importance of the leukotrienes inallergic disorders as well. Thus, after allergen provocation, a markedincrease in the LT concentration in the nasal lavage fluid of patientswith allergic rhinitis was detected both in the early phase and in thelate phase. Creticos, P. S., S. P. Peters, N. F. Adkinson, R. M.Naclerio, E. C. Hayes, P. S. Norman, L. M. Lichtenstein, N. Eng. J. Med.310:1626 (1984). In addition, treatment with clinically efficaciousantihistamines, such as azelastine, has shown a reduction in theformation of the cysteinyl-leukotrines, establishing a correlativerelationship of allergic reaction symptoms to the degree of leukotrieneformation and, thus, CysLT receptor activation. Achterrath-Tuckermann,U., Th. Simmet, W. Luck, I. Szelenyi, B. A. Peskar, Agents and Actions24:217, 1988; Shin, M. H., F. M. Baroody, D. Proud, A. Kagey-Sobotka, L.M. Lichtenstein, M. Naclerio, Clin. Exp. Allergy 22:289, 1992.

U.S. Pat. No. 6,194,432 B1 discloses a method for using leukotrieneantagonist drugs to prevent and treat recurrent primary headachesincluding migraine headaches.

U.S. Pat. No. 5,977,177 discloses certain substituted phenyl derivativecompounds are modulators of endothelin and, as such, are useful intreating many different conditions including asthma.

U.S. Pat. No. 4,853,398 discloses certain benzene derivative compoundsare selective antagonists of leukotrienes and, as such, are useful intreating allergic disorders such as asthma.

European Patent Application No. EP 28063 A1 and UK Patent ApplicationNo. GB 2058785 disclose certain phenol derivative compounds areantagonists of slow reacting substance of anaphylaxis and, as such, areuseful in treating asthma, hay fever and skin afflictions.

Brown, F. J. et al J. Med. Chem. 32, p. 807-826 (1989) discloses certainhydroxyacetophenone derivative compounds are antagonists of leukotrienesand, as such, play a role in treating asthma.

International Patent Application Publication No. WO 2001056990 A2 andU.S. Pat. No. 6,800,651 B2 disclose certain pyridine derivativecompounds are potentiators of metabotropic glutamate receptor function,specifically; potentiators of mGlu2 receptor function and, as such, areuseful in the treatment of many different conditions including anxietyand migraine headache.

International Patent Application Publication No. WO 2004018386 andPinkerton, A. B. et al Bioorg. Med. Chem. Lett., 14, p. 5329-5332 (2004)disclose certain acetophenone derivative compounds are potentiators ofglutamate receptor function, specifically; potentiators of mGlu2receptor function and, as such, are useful in the treatment of manydifferent conditions including anxiety, schizophrenia and migraineheadache.

Recently, Pinkerton, A. B. et al Bioorg. Med. Chem. Lett., 14, p.5867-5872 (2004) disclose certain 4-thiopyridyl acetophenone derivativecompounds are potentiators of glutamate receptor function, specifically;potentiators of mGlu2 receptor function and, as such, may be useful inthe treatment of CNS disorders including anxiety, schizophrenia andepilepsy.

The present invention provides compounds of formula I that arepotentiators of the mGlu2 receptor and antagonists of the CysLT1receptor. As such, compounds of formula I would provide a means to treatdisorders associated with glutamate or leukotrienes. In addition, it isanticipated that in disorders with a glutamate and leukotriene componentto the onset, propagation and/or symptoms, the compounds of formula Iwill provide an effective treatment for the patient. The medicalconsequences of such glutamate dysfunction make the abatement of theseneurological processes an important therapeutic goal.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I:

wherein

R¹ is selected from the group consisting of C1-C5 alkyl, C3-C7cycloalkyl, C4-C8 cycloalkylalkyl, phenyl and substituted phenyl;

R² is selected from the group consisting of hydrogen, C1-C5 alkyl,substituted C1-C5 alkyl, halo, phenyl, substituted phenyl, C1-C3fluoroalkyl, CN, CO₂R³, thiophenyl, substituted thiophenyl, thiazolyl,substituted thiazoyl, furanyl, substituted furanyl, pyridinyl,substituted pyridinyl, oxazolyl, substituted oxazolyl, isothiazolyl,substituted isothiazoyl, isoxazolyl, substituted isoxazolyl,1,2,4-oxadiazolyl, substituted 1,2,4-oxadiazolyl, pyrimidinyl,substituted pyrimidinyl, pyridazinyl and substituted pyridazinyl;

X is selected from the group consisting of O, S(O)_(m), and NR³;

Y is selected from the group consisting of C1-C3 alkanediyl andsubstituted C1-C3 alkanediyl;

Ar₁ and Ar₂ are independently selected from the group consisting ofphenylene, substituted phenylene, thiophenediyl, substitutedthiophenediyl, thiazolediyl, substituted thiazolediyl, furanediyl,substituted furanediyl, pyridinediyl, substituted pyridinediyl,oxazolediyl, substituted oxazolediyl, isothiazolediyl, substitutedisothiazolediyl, isoxazolediyl, substituted isoxazolediyl,pyrimidinediyl, substituted pyrimidinediyl, pyridazinediyl, substitutedpyridazinediyl and 1,2,4-oxadiazole-3,5-diyl;

L is selected from the group consisting of C1-C5 alkanediyl, substitutedC1-C5 alkanediyl, and -G-C(═W)-J-;

W is CR³R³, O or NR³;

G and J are independently selected from the group consisting of a bondand C1-C3 alkanediyl;

R³ is independently hydrogen or C1-C5 alkyl;

Z is selected from the group consisting of (CH₂)_(n)COOH,

m is 0, 1, or 2;

n and q are independently 0, 1, 2 or 3;

and

pharmaceutically acceptable salts thereof.

In another embodiment, the present invention provides a compound offormula I wherein Z is selected from the group consisting of(CH₂)_(n)COOH,

The present invention also provides for novel pharmaceuticalcompositions, comprising a compound of the formula I and apharmaceutically acceptable diluent.

Because the compounds of formula I are potentiators of the mGlu2receptor, the compounds of formula I are useful for the treatment of avariety of neurological and psychiatric disorders associated withglutamate dysfunction, including: acute neurological and psychiatricdisorders such as cerebral deficits subsequent to cardiac bypass surgeryand grafting, stroke, cerebral ischemia, spinal cord trauma, headtrauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage,dementia (including AIDS-induced dementia), Alzheimer's disease,Huntington's Chorea, amyotrophic lateral sclerosis, multiple sclerosis,ocular damage, retinopathy, cognitive disorders, idiopathic anddrug-induced Parkinson's disease, muscular spasms and disordersassociated with muscular spasticity including tremors, epilepsy,convulsions, migraine (including migraine headache), urinaryincontinence, substance tolerance, substance withdrawal (including,substances such as opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis,schizophrenia, anxiety (including generalized anxiety disorder, panicdisorder, and obsessive compulsive disorder), mood disorders (includingdepression, mania, bipolar disorders), trigeminal neuralgia, hearingloss, tinnitus, macular degeneration of the eye, emesis, brain edema,pain (including acute and chronic pain states, severe pain, intractablepain, neuropathic pain, and post-traumatic pain), tardive dyskinesia,sleep disorders (including narcolepsy), attention deficit/hyperactivitydisorder, and conduct disorder.

In another embodiment the present invention provides methods of treatingneurological and psychiatric disorders associated with glutamatedysfunction, comprising administering to a patient in need thereof aneffective amount of a compound of formula I. That is, the presentinvention provides for the use of a compound of formula I orpharmaceutical composition thereof for the treatment neurological andpsychiatric disorders associated with glutamate dysfunction.

Of the disorders above, the treatment of migraine, anxiety,schizophrenia, and epilepsy are of particular importance.

In a preferred embodiment the present invention provides a method oftreating migraine, comprising administering to a patient in need thereofan effective amount of a compound of formula I.

In another preferred embodiment the present invention provides a methodof treating anxiety, comprising administering to a patient in needthereof an effective amount of a compound of formula I. Particularlypreferred anxiety disorders are generalized anxiety disorder, panicdisorder, and obsessive compulsive disorder.

In another preferred embodiment the present invention provides a methodof treating schizophrenia, comprising administering to a patient in needthereof an effective amount of a compound of formula I.

In yet another preferred embodiment the present invention provides theuse of a compound of formula I for the manufacture of a medicament forthe treatment of neurological and psychiatric disorders associated withglutamate dysfunction.

In yet another preferred embodiment the present invention provides acompound of formula I for use as a medicament.

In yet another preferred embodiment the present invention provides theuse of a compound of formula I for the manufacture of a medicament forthe treatment of migraine.

In yet another preferred embodiment the present invention provides apharmaceutical composition for the treatment of neurological andpsychiatric disorders associated with glutamate dysfunction containingas an active ingredient a compound of formula I.

In yet another preferred embodiment the present invention provides amethod of treating epilepsy, comprising administering to a patient inneed thereof an effective amount of a compound of formula I.

Because such potentiators, including the compounds of formula I,positively modulate metabotropic glutamate receptor response toglutamate, it is an advantage that the present methods utilizeendogenous glutamate.

Because such potentiators positively modulate metabotropic glutamatereceptor response to glutamate agonists it is understood that thepresent invention extends to the treatment of neurological andpsychiatric disorders associated with glutamate dysfunction byadministering an effective amount of a metabotropic glutamatepotentiator, including the compounds of formula I, in combination with apotentiated amount of a metabotropic glutamate receptor agonist. Such acombination may be advantageous in that it may augment the activity andselectivity of an agonist of metabotropic glutamate receptors, inparticular a potentiator of mGlu2 receptors.

Because many the compounds of formula I are antagonists of the CysLT1receptor, many of the compounds of formula I are useful for thetreatment of a variety of disorders mediated by one or more leukotrienessuch as inflammatory and allergic disorders associated with leukotrienemediation including inflammatory bowel syndrome, inflammatory boweldisease, arthritis, asthma, psoriasis, and thrombotic disease.

In another embodiment the present invention provides methods of treatinga variety of disorders mediated by one or more leukotrienes, comprisingadministering to a patient in need thereof an effective amount of acompound of formula I. That is, the present invention provides for theuse of a compound of formula I or pharmaceutical composition thereof forthe treatment inflammatory and allergic disorders associated withleukotriene mediation.

In a preferred embodiment the present invention provides a method oftreating asthma, comprising administering to a patient in need thereofan effective amount of a compound of formula I.

In another embodiment the present invention provides a process forpreparing a compound of formula I or a pharmaceutically acceptable saltthereof.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides methods of potentiating metabotropic glutamatereceptors, in particular mGlu2 receptors. In the present methods aneffective amount of a potentiator of metabotropic glutamate 2 receptors,including a compound of formula I, is administered which positivelymodulates the effect of glutamate or glutamate agonists on the subjectreceptor.

Before describing the present invention in greater detail, it isunderstood that the invention in its broadest sense is not limited toparticular embodiments described herein, as variations of the particularembodiments described herein are within the scope of the claimedinvention.

Thus, compounds useful in the present invention are those which arepotentiators of metabotropic glutamate receptors, particularly, thosethat potentiate the effects of glutamate and glutamate agonists at mGlu2metabotropic glutamate receptors, and even more particularly, those thatpotentiate the effects of glutamate and glutamate agonists at mGlu2receptors. Useful compounds are varied in structure, and so long as theyembrace the above properties, they are suitable for use in the presentinvention. Preferred compounds include, but are not limited to, thosedescribed herein.

The compounds of formula I potentiate the function of glutamatereceptors. Specifically, the compounds of formula I are potentiators ofthe mGlu2 receptor.

Compounds of in the present invention also include those which aremodulators of leukotriene receptors, particularly, those that antagonizethe CysLT1 receptor.

As used herein, the following terms have the meanings indicated:

The term “C1-C5 alkyl” refers to a straight or branched alkyl chainhaving from one to five carbon atoms, and includes methyl, ethyl,propyl, iso-propyl, butyl, iso-butyl, sec-butyl, t-butyl, pentyl and thelike. Particular values of “C1-C5 alkyl” are methyl, ethyl, n-propyl andiso-propyl.

The term “alkyl” refers to a monovalent aliphatic hydrocarbon. Withinthe meaning of “alkyl” is the term “C1-C3 alkyl”.

The term “C1-C3 alkyl” refers to a straight or branched alkyl chainhaving from one to three carbon atoms, and includes methyl, ethyl,propyl, iso-propyl, and the like.

The term “substituted C1-C5 alkyl” refers to a straight or branchedalkyl chain having from one to five carbon atoms, and includes methyl,ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, t-butyl andpentyl having from 1 to 3 substituents selected from the groupconsisting of hydroxy, halogen, azido, alkoxy, acyloxy, carboxy,alkoxycarbonyl, amido, substituted amido, amino, acylamino,sulfonylamido, sulfonamide, phenyl, substituted phenyl, phenoxy,substituted phenoxy, benzyloxy, substituted benzyloxy, pyridyl,substituted pyridyl, thienyl, and substituted thienyl.

The term “C1-C5 alkanediyl” refers to a straight or branched divalentalkyl chain having from one to five carbon atoms, and includes methyleneand ethane-1,1-diyl.

The term “substituted C1-C5 alkanediyl” refers to a straight or brancheddivalent alkyl chain having from one to five carbon atoms, and includesmethylene having a substituent selected from the group consisting ofhydroxyl, fluoro, azido, methoxy, amino, acetylamino andmethylsulfonamide. Particular values of “substituted C1-C5 alkanediyl”are CH(OH), CH(F), CHN₃, CH(OCH₃), CHNH₂, CHNH(C═O)CH₃, CHNH(SO₂)CH₃.

The term “C1-C3 alkanediyl” refers to a straight or branched divalentalkyl chain having from one to three carbon atoms, and includesmethylene.

The term “substituted C1-C3 alkanediyl” refers to a straight or branchedalkyl chain having from one to three carbon atoms, and includesmethylene, having from 1 or 2 substituents selected from the groupconsisting of hydroxy, halogen, azido, alkoxy, acyloxy, carboxy,alkoxycarbonyl, amido, substituted amido, amino, acylamino,sulfonylamido, sulfonamide, phenyl, substituted phenyl, pyridyl,substituted pyridyl, thienyl, and substituted thienyl

The term “halogen or halo” refers to chloro, fluoro, bromo or iodo.

The term “C1-C3 fluoro alkyl” refers to an alkyl chain having from oneto three carbon atoms substituted with one or more fluorine atoms, andincludes fluoromethyl, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and the like. A particularvalue of “C1-C3 fluoro alkyl” is trifluoromethyl.

The term “alkoxy” refers to a straight or branched alkyl chain attachedto an oxygen atom. Within the meaning of “alkoxy” is the term “C1-C4alkoxy”.

The term “C1-C4 alkoxy” refers to straight or branched alkyl chainhaving from one to four carbon atoms attached to an oxygen atom, andincludes methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,sec-butoxy, t-butoxy, and the like.

The term “substituted alkoxy” refers to a straight or branched alkylchain attached to an oxygen atom having from 1 to 3 substituents. Withinthe meaning of “substituted alkoxy” is the term “substituted C1-C4alkoxy”.

The term “substituted C1-C4 alkoxy” refers to straight or branched alkylchain having from one to four carbon atoms attached to an oxygen atom,and includes methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,sec-butoxy, t-butoxy, and the like, having from 1 to 3 substituentsselected from the group consisting of hydroxy, halogen, alkoxy, carboxy,amido, substituted amido, amino, acylamino, sulfonylamido, sulfonamide,phenyl, and substituted phenyl; and when one or more of the substituentsis hydroxy, halogen, alkoxy, amino, acylamino, and sulfonamide, thenthose substituents are not attached to the same carbon as the alkoxyoxygen atom.

The term “C3-C7 cycloalkyl” refers to saturated cyclic alkyl grouphaving from three to seven carbon atoms and includes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term “C4-C8 cycloalkylalkyl” refers to saturated cyclic alkyl grouphaving from three to seven carbon atoms linked to the point ofsubstitution by a divalent unsubstituted saturated straight-chain orbranched-chain hydrocarbon radical having at least 1 carbon atom andincludes, cyclopropylmethyl, cyclopropyl-2-propyl, cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl and the like.

The terms “phenyl and substituted phenyl” or “phenylene and substitutedphenylene” refer to a monovalent or divalent radical, respectively, ofthe formula

wherein R_(a) is from 1 to 3 groups independently selected from thegroup consisting of hydrogen, hydroxy, alkyl, substituted alkyl,cycloalkyl, alkoxy, substituted alkoxy, halogen, carboxy,alkoxycarbonyl, amido, substituted amido, amino, acylamino,sulfonylamido, sulfonamide, cyano, nitro, phenyl, and substitutedphenyl. Particular values of R_(a) are hydrogen, methoxy and fluoro.Particular values of R_(a) are hydrogen, methoxy and fluoro.

The terms “thiophenyl and substituted thiophenyl” or “thiophenediyl andsubstituted thiophenediyl” refer to a monovalent or divalent radical,respectively, of the formula

wherein R_(b) is 1 or 2 groups independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, alkoxy,substituted alkoxy, halogen, carboxy, alkoxycarbonyl, amido, substitutedamido, amino, acylamino, sulfonylamido, sulfonamide, cyano, nitro,phenyl, and substituted phenyl. A particular value of R_(b) is hydrogen.

The terms “pyridinyl and substituted pyridinyl” or “pyridinediyl andsubstituted pyridinediyl” refer to a monovalent or divalent radical,respectively, of the formula

wherein R_(c) is from 1 to 3 groups independently selected from thegroup consisting of hydrogen, hydroxy, alkyl, substituted alkyl,cycloalkyl, alkoxy, substituted alkoxy, halogen, carboxy,alkoxycarbonyl, amido, substituted amido, amino, acylamino,sulfonylamido, sulfonamide, cyano, nitro, phenyl, and substitutedphenyl. A particular value of R_(c) is hydrogen.

The terms “thiazolyl and substituted thiazolyl” or “thiazolediyl andsubstituted thiazolediyl” refer to a monovalent or divalent radical,respectively, of the formula

wherein R_(d) is 1 or 2 groups independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, alkoxy,substituted alkoxy, halogen, carboxy, alkoxycarbonyl, amido, substitutedamido, amino, acylamino, sulfonylamido, sulfonamide, cyano, nitro,phenyl, and substituted phenyl. A particular value of R_(d) is hydrogen.

The terms “furanyl and substituted furanyl” or “furanediyl andsubstituted furanediyl” refer to a monovalent or divalent radical,respectively, of the formula

wherein R_(e) is 1 or 2 groups independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, alkoxy,substituted alkoxy, halogen, carboxy, alkoxycarbonyl, amido, substitutedamido, amino, acylamino, sulfonylamido, sulfonamide, cyano, nitro,phenyl, and substituted phenyl. A particular value of R_(e) is hydrogen.

The terms “isothiazolyl and substituted isothiazoyl” or “isothiazolediyland substituted isothiazolediyl” refer to a monovalent or divalentradical, respectively, of the formula

wherein R_(f) is 1 or 2 groups independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, alkoxy,substituted alkoxy, halogen, carboxy, alkoxycarbonyl, amido, substitutedamido, amino, acylamino, sulfonylamido, sulfonamide, cyano, nitro,phenyl, and substituted phenyl. A particular value of R_(f) is hydrogen.

The terms “isoxazolyl and substituted isoxazolyl” or “isoxazolediyl andsubstituted isoxazolediyl” refer to a monovalent or divalent radical,respectively, of the formula

wherein R_(g) is 1 or 2 groups independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, alkoxy,substituted alkoxy, halogen, carboxy, alkoxycarbonyl, amido, substitutedamido, amino, acylamino, sulfonylamido, sulfonamide, cyano, nitro,phenyl, and substituted phenyl. A particular value of R_(g) is hydrogen.

The terms “1,2,4-oxadiazolyl and substituted 1,2,4-oxadiazolyl” or“1,2,4-oxadiazole-3,5-diyl” refer to a monovalent radical or divalentradical lacking R_(h), respectively, of the formula

wherein R_(h) is independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, alkoxy, substitutedalkoxy, halogen, carboxy, alkoxycarbonyl, amido, substituted amido,amino, acylamino, sulfonylamido, sulfonamide, cyano, nitro, phenyl, andsubstituted phenyl. A particular value of R_(h) is hydrogen.

The terms “pyrimidinyl and substituted pyrimidinyl” or “pyrimidinediyland substituted pyrimidinediyl” refer to a monovalent or divalentradical, respectively, of the formula

wherein R_(i) is from 1 to 3 groups independently selected from thegroup consisting of hydrogen, hydroxy, alkyl, substituted alkyl,cycloalkyl, alkoxy, substituted alkoxy, halogen, carboxy,alkoxycarbonyl, amido, substituted amido, amino, acylamino,sulfonylamido, sulfonamide, cyano, nitro, phenyl, and substitutedphenyl. A particular value of R_(i) is hydrogen.

The terms “pyridazinyl and substituted pyridazinyl” or “pyridazinediyland substituted pyridazinediyl” refer to a monovalent or divalentradical, respectively, of the formula

wherein R_(j) is from 1 to 3 groups independently selected from thegroup consisting of hydrogen, hydroxy, alkyl, substituted alkyl,cycloalkyl, alkoxy, substituted alkoxy, halogen, carboxy,alkoxycarbonyl, amido, substituted amido, amino, acylamino,sulfonylamido, sulfonamide, cyano, nitro, phenyl, and substitutedphenyl. A particular value of R_(j) is hydrogen.

The terms “oxazolyl and substituted oxazolyl” or “oxazolediyl andsubstituted oxazolediyl” refer to a monovalent or divalent radical,respectively, of the formula

wherein R₁ is 1 or 2 groups independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, alkoxy,substituted alkoxy, halogen, carboxy, alkoxycarbonyl, amido, substitutedamido, amino, acylamino, sulfonylamido, sulfonamide, cyano, nitro,phenyl, and substituted phenyl. A particular value of R₁ is hydrogen.

The term “carboxy” refers to a radical of the formula

The term “alkoxycarbonyl” refers to a radical of the formula

wherein R_(k) is selected from the group consisting of alkyl,substituted alkyl, phenyl and substituted phenyl. Particular values ofR_(k) are methyl and ethyl.

The term “amido” refers to a radical of the formula

The term “substituted amido” refers to a radical of the formula

wherein R_(m) is selected from the group consisting of alkyl and R_(n)is selected from the group consisting of hydrogen, alkyl, phenyl andsubstituted phenyl. A particular value for R_(m) is methyl. Particularvalues for R_(n) are hydrogen and methyl.

The term “acylamino” refers to a radical of the formula

wherein R_(o) is selected from the group consisting of alkyl, phenyl,and substituted phenyl. A particular value of R_(o) is methyl.

The term “sulfonylamido” refers to a radical of the formula

wherein R_(p) is selected from the group consisting of alkyl, phenyl,and substituted phenyl; and R_(p) is selected from the group consistingof hydrogen and alkyl. A particular value for R_(p) is methyl.Particular values for R_(p) are hydrogen and methyl.

The term “sulfonamide” refers to a radical of the formula

wherein R_(q) is selected from the group consisting of alkyl, phenyl,and substituted phenyl. A particular value of R_(q) is methyl.

As is readily apparent to those skilled in the art, the compounds offormula I may exist as tautomers. Where tautomers exist, each tautomericform and mixtures thereof, are contemplated as included in the presentinvention. When any reference in this application to one of the specifictautomers of the compounds of formula I is given, it is understood toencompass every tautomeric form and mixtures thereof. For example, wherethe group Z is tetrazolyl, a compound of formula I exists as tautomer Iand tautomer II. As such, it is understood any reference to a compoundof formula I where the group Z is tetrazolyl as tautomer I encompassestautomer II as well as mixtures of tautomer I and tautomer II.

It is understood that compounds of the present invention may exist asstereoisomers. All enantiomers, diastereomers, and mixtures thereof, arecontemplated within the present invention. Where specificstereochemistries are identified in this application, theCahn-Ingold-Prelog designations of (R)- and (S)- and the cis- andtrans-designation of relative stereochemistry are used to refer tospecific isomers and relative stereochemistry. Known optical rotationsare designated by (+) and (−) for dextrorotatary and levorotatary,respectively. Where a chiral compound is resolved into its enantiomers,but absolute configurations are not determined, the isomers aredesignated as isomer 1, isomer 2, etc.

Specific stereoisomers can be prepared by stereospecific synthesis usingenantiomerically pure or enriched starting materials. The specificstereoisomers of either starting materials or compounds of formula I canbe resolved by techniques well known in the art, such as those found inStereochemistry of Organic Compounds, E. I. Eliel and S. H. Wilen (Wiley1994) and Enantiomers, Racemates, and Resolutions, J. Jacques, A.Collet, and S. H. Wilen (Wiley 1991), including chromatography on chiralstationary phases, enzymatic resolutions, or fractional crystallizationor chromatography of diastereomers formed for that purpose, such asdiastereomeric salts.

While all enantiomers, diastereomers, and mixtures thereof, arecontemplated within the present invention, preferred embodiments aresingle enantiomers and single diastereomers.

The terms “Ar₁ and Ar₂” refer to five or six member aryl or heterocyclicrings independently selected from the group consisting of phenylene,substituted phenylene, thiophenediyl, substituted thiophenediyl,thiazolediyl, substituted thiazolediyl, furanediyl, substitutedfuranediyl, pyridinediyl, substituted pyridinediyl, oxazolediyl,substituted oxazolediyl, isothiazolediyl, substituted isothiazolediyl,isoxazolediyl, substituted isoxazolediyl, pyrimidinediyl, substitutedpyrimidinediyl, pyridazinediyl, substituted pyridazinediyl and1,2,4-oxadiazole-3,5-diyl. It is understood that Ar₁ and Ar₂ being atleast bi-radical may be attached in a 1-2, 1-3 or 1-4 regioisomericposition depending on the nature of the ring and the number and locationof substituents. It is further understood that the present inventionencompasses all possible regioisomeric combinations of attachment to Ar₁and Ar₂. For example, where Ar₁ is phenylene there exists three possibleregioisomers, designated as 1-2 (ortho or o-), 1-3 (meta or m-) and 1-4(para or p-), all of which are encompassed in the present invention fora compound of formula I where Ar₁ is phenylene.

The term “pharmaceutically acceptable salt” refers to an addition saltthat exists in conjunction with the acidic and/or basic portion of acompound of formula I. Such salts include the pharmaceuticallyacceptable salts listed in Handbook of Pharmaceutical Salts: Properties,Selection and Use, P. H. Stahl and C. G. Wermuth (Eds.), Wiley-VCH, NewYork, 2002 which are known to the skilled artisan. Pharmaceuticallyacceptable salts that are acid addition are formed when a compound offormula I and the intermediates described herein containing a basicfunctionality are reacted with a pharmaceutically acceptable acid.Pharmaceutically acceptable acids commonly employed to form such acidaddition salts include inorganic acids, such as hydrochloric,hydrobromic, nitric, sulphuric or phosphoric acids, and organic acidssuch as acetic, citric, esylic, fumaric, glycolic, glucuronic, glutaric,lactic, maleic, malic, mandelic, mesylic, napadisylic, oxalic, succinic,tartaric, salicyclic, o-acetoxybenzoic, or p-toluene-sulphonic.Pharmaceutically acceptable salts that are base addition are formed whena compound of formula I and the intermediates described hereincontaining a acidic functionality are reacted with a pharmaceuticallyacceptable base. Pharmaceutically acceptable bases commonly employed toform base addition salts include organic bases such as ammonia,arginine, benethamine, benzathine, benzylamine, betaine, butylamine,choline, dicyclohexylamine, diethanolamine, diethylamine,ethylenediamine, glucosamine, imidazole, lysine, piperazine, procaine,and inorganic bases such as calcium, potassium, sodium and zinc salts ofhydroxide, carbonate or bicarbonate and the like.

In addition to pharmaceutically acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of compounds or in the preparation of other, for examplepharmaceutically-acceptable, acid addition salts, or are useful foridentification, characterization or purification.

The term “protecting group or Pg,” as used herein, refers to thosegroups intended to protect or block functional groups againstundesirable reactions during synthetic procedures. In the case of anamino or hydroxyl functional group, the suitable protecting group usedwill depend upon the conditions that will be employed in subsequentreaction steps wherein protection is required. For example, it may bedesirable to employ the protection of multiple functional groups, suchas amino and hydroxyl, and control their protection and deprotectionindependently. Commonly used amino and hydroxyl protecting groups aredisclosed in Protective Groups In Organic Synthesis, T. W. Greene and P.G. M. Wuts 3rd Ed. (John Wiley & Sons, New York (1999)). Suitable aminoprotecting groups include acyl groups such as formyl, acetyl, propionyl,pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, alpha-chlorobutyryl,benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like;sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like,carbamate forming groups such as benzyloxycarbonyl,p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl, alpha,alpha-dimethyl-3,5-dimethoxy-benzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl andthe like; and silyl groups such as trimethylsilyl and the like.Preferred suitable amino protecting groups are acetyl,methyloxycarbonyl, benzoyl, pivaloyl, allyloxycarbonyl, t-butylacetyl,benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). Suitablehydroxyl protecting groups include ethers such as methoxymethyl,1-ethoxyethyl, tert-butyl, allyl, benzyl, tetrahydropyranyl and thelike; silyl ethers such as trimethylsilyl, triethylsilyl,triisopropylsilyl, tert-butyldimethylsilyl and the like; esters such asformate, acetate, pivaloate, benzoate and the like; and sulfonates suchas mesylate, benzylsulfonate, tosylate and the like. Preferred suitablehydroxyl protecting groups are acetyl, trimethylsilyl,triisopropylsilyl, tert-butyldimethylsilyl and benzyl.

As with any group of pharmaceutically active compounds, some groups arepreferred in their end use application. Preferred embodiments for acompound of formula I of the present invention are given below.

Compounds in which R¹ is C3-C7 cycloalkyl or C4-C8 cycloalkylalkyl arepreferred. Compounds in which R¹ is C1-C5 alkyl are more preferred.Compounds in which R¹ is methyl are even more preferred.

Compounds in which R² is phenyl, substituted phenyl, thiophenyl,substituted thiophenyl, thiazolyl, substituted thiazolyl, pyridinyl, orsubstituted pyridinyl are preferred. Compounds in which R² is C1-C5alkyl, halo or C1-C3 fluoroalkyl are more preferred. Compounds in whichR² is methyl, propyl, trifluoromethyl, or chloro are even morepreferred.

Compounds in which X is S(O)_(m) where m is 0, 1 or 2 are preferred.Compounds in which X is O are more preferred.

Compounds in which Y is C1-C3 alkanediyl are preferred. Compounds inwhich Y is methylene are more preferred.

Compounds in which Ar₁ is phenylene are preferred.

Compounds in which Ar₁ and Ar₂ are independently phenylene orpyridinediyl are preferred.

Compounds in which Ar₁ is substituted phenylene,1,2,4-oxadiazol-3,5-diyl or substituted pyridinediyl are preferred.Compounds in which Ar₁ is phenylene or pyridinediyl, either attached inthe 1-3 position, are more preferred. Compounds in which Ar₁ isphenylene or pyridinediyl, either ring attached in the 1-4 position, areeven more preferred.

Compounds in which Ar₂ is phenylene are preferred.

Compounds in which Ar₂ is substituted phenylene or substitutedpyridinediyl are preferred. Compounds in which Ar₂ is phenylene orpyridinediyl are more preferred.

Compounds in which Ar₂ is pyridinediyl attached in the 1-4 or 1-3position are even more preferred.

Compounds in which Ar₁ and Ar₂ are independently phenylene orpyridinediyl are preferred.

Compounds in which Ar₁ is phenylene are preferred.

Compounds in which Ar₂ is pyridinediyl are preferred.

Compounds in which Ar₂ is attached at the 1-4 position are preferred.

Compounds in which Ar₂ is attached at the 1-3 position are preferred.

Compounds in which Ar₁ is attached at the 1-3 position or 1-4 positionare preferred.

Compounds in which L is C1-C5 alkanediyl, substituted C1-C5 alkanediylor C(═W) where W is CH₂ or O are preferred. Compounds in which L is—CH(OH)—, —CH(F)— or —CH₂— are more preferred.

Compounds in which Z is

are preferred. Compounds in which Z is

are more preferred. Compounds in which Z is

are even more preferred.

A compound of formula I as described above wherein

R¹ is methyl or ethyl;

R² is selected from the group consisting of methyl, ethyl, n-propyl,iso-propyl, fluoro, chloro, iodo, phenyl, 4-fluorophenyl,trifluoromethyl, CN, 2-thiophenyl, 3-thiophenyl, 2-thiazolyl,2-pyridinyl, 3-pyridinyl, and 4-pyridinyl;

X is selected from the group consisting of O, S, SO₂, NH and NCH₃;

Y is methylene;

Ar₁ is phenylene or 1,2,4-oxadiazole-3,5-diyl;

Ar₂ is selected from the group consisting of phenylene, fluorophenylene,methoxyphenylene and pyridinediyl;

L is selected from the group consisting of CH₂, CHCH₃, CH(OH), CH(F),CHN₃, CH(OCH₃), CHNH₂, CHNH(C═O)CH₃, CHNH(SO₂)CH₃, C═O, and CH═CH₂;

Z is selected from the group consisting of (CH₂)_(n)COOH,

n is 0; and

q is 0 is preferred.

A compound of formula I selected from the group consisting of(+)-3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoicacid (isomer 1) and(−)-3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoicacid (isomer 2) is preferred. A compound of formula I which is3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(S)-hydroxymethyl}-benzoicacid is more preferred.

Further embodiments of the invention include a process for preparing thecompound of formula I, or a pharmaceutically acceptable salt thereof,comprising

(A) for a compound of formula I where Z is tetrazolyl,

cycloaddition of a compound of formula II where R¹⁰ is cyano with anazide reagent;

(B) for a compound of formula I where Z is COOH,

hydrolysis of a compound of formula II wherein R¹⁰ is COOR¹⁴ and R¹⁴ isselected from the group consisting of C1-C5 alkyl, phenyl and benzyl;

(C) for a compound of formula I where Z is COOH,

hydrolysis of a compound of formula II where R¹⁰ is cyano; and

(D) for a compound of formula I

where Z is

cyclocondensating a compound of formula II where R¹⁰ is an acyl chloride

whereafter, when a pharmaceutically acceptable salt of the compound offormula I is required, it is obtained by reacting the acid of formula Iwith a physiologically acceptable base or by reacting a basic compoundof formula I with a physiologically acceptable acid or by any otherconventional procedure.

A further embodiment of the present invention provides intermediatecompounds useful for the preparation of a compound of formula I. Morespecifically, the present invention provides a compound of formula II

wherein

R¹, R², X, Y, Ar₁, Ar₂ and L are defined as above; and

R¹⁰ is CN or COOR¹⁴ in which R¹⁴ is selected from the group consistingof C1-C5 alkyl, phenyl and benzyl. A particular value of R¹⁴ is methyl.

A further embodiment of the present invention provides a process forpreparing3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(S)-hydroxymethyl}-benzoicacid or a pharmaceutically acceptable salt thereof,

comprising

(i) alkylating 2,4-dihydroxy-3-propyl-acetophenone with3-[4-(methanesulfonyloxymethylphenyl)-(S)-acetoxymethyl]-benzonitrile inthe presence of potassium carbonate to afford3-{[4-(4-acetyl-3-hydroxy-2-propylphenoxymethyl)-phenyl]-(S)-acetoxymethyl}-benzonitrile;

(ii) hydrolyzing3-{[4-(4-acetyl-3-hydroxy-2-propylphenoxymethyl)-phenyl]-(S)-acetoxymethyl}-benzonitrilein the presence of potassium hydroxide wherein the hydrolysis reactionis followed by acidification with hydrochloric acid to afford3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(S)-hydroxymethyl}-benzoicacid; whereafter, when a pharmaceutically acceptable salt of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(S)-hydroxymethyl}benzoicacid is required, it is obtained by reacting3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(S)-hydroxymethyl}-benzoicacid with a physiologically acceptable base or by any other conventionalprocedure.

A further embodiment of the present invention provides the abovementioned starting3-[4-(methanesulfonyloxymethylphenyl)-(S)-acetoxymethyl]-benzonitrile isprepared using a process comprising

(i) arylating enantioselectively 3-cyanobenzaldehyde with2,4,6-tris-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-cylcotriboroxanein the presence of a dialkyl zinc and chiral catalyst wherein thedialkyl zinc is diethyl zinc; and the chiral catalyst is(R)-(−)-2-piperidino-1,1,2-triphenyl ethanol to afford3-{[4-(tert-butyldimethylsilanyloxymethyl)phenyl]-(S)-hydroxymethyl}-benzonitrile;

(ii) acylating3-{[4-(tert-butyldimethylsilanyloxymethyl)phenyl]-(S)-hydroxymethyl}-benzonitrilewith acetic anhydride whereafter hydrolyzing the4-(tert-butyl-dimethyl-silanyl group with hydrochloric acid to afford3-[4-(hydroxymethylphenyl)-(S)-acetoxymethyl]-benzonitrile;

(iii) sulfonating3-[4-(hydroxymethylphenyl)-(S)-acetoxymethyl]-benzonitrile with methanesulfonyl chloride to afford3-[4-(methanesulfonyloxymethylphenyl)-(S)-acetoxymethyl]-benzonitrile.

A further embodiment of the present invention provides intermediatecompounds useful for the preparation of a compound of formula I. Morespecifically, the present invention provides a compound which is3-[4-(hydroxymethylphenyl)-(S)-acetoxymethyl]-benzonitrile.

Compounds of the present invention may be made by a process which isanalogous to one known in the chemical art for the production ofstructurally analogous compounds or by a novel process described herein.Such processes useful for the manufacture of a compound of formula I asdefined above are provided as further features of the invention and areillustrated by the following procedures in which, unless otherwisespecified, the meanings of the generic radicals are as defined above andall reagents are well known and appreciated in the art.

Generally, a compound of formula I may be prepared from a compound offormula II where R¹⁰ represents a precursor to Z (Reaction Scheme A,step a). More specifically, a compound of formula II where R¹⁰ iscarboxylic acid ester or nitrile is reacted with a suitable base such aspotassium hydroxide in a suitable solvent such as water to provide acompound of formula I where Z is carboxylic acid. Additionally, acompound of formula II where R¹⁰ is cyano is reacted with an azidereagent to provide a compound of formula I where Z is tetrazolyl. Azidereagents include HN₃ wherein HN₃ is provided from the reaction of sodiumazide and a protic acid such as triethylamine hydrochloride or ammoniumchloride. The reaction is conveniently in a solvent such solutions ofwater and an organic co-solvent wherein the organic cosolvent is analcohol such as isopropyl alcohol or a tertiary amide such asN-methylpyrrolidinone. Other examples of azide reagents includetransition metal azide complexes such as provided from the reaction ofzinc bromide and sodium azide, as well as the trialkylsilylazides suchas trimethylsilylazide. A compound of formula II where R¹⁰ is an acidhalide is reacted in one or more steps with cyclocondensating agents toprovide a compound of formula I where Z is

A compound of formula of II may be prepared from a compound of formulaIII (Reaction Scheme A, step b) or, alternatively, from a compound offormula V (Reaction Scheme A, step c). More specifically in step b, acompound of formula III where X is O is reacted under Mitsunobuconditions with a compound of formula IV where R¹¹ is OH in the presenceof an organophosphine such as tributylphosphine and an appropriateazodicarbonyl reagent such as 1,1′-(azodicarbonyl)dipiperidine toprovide a compound of formula II. Suitable solvents include toluene anddichloromethane. In step b, a compound of formula II may also beprepared by reacting a compound of formula III where X is O, S, NH witha compound of formula IV where R¹¹ is a leaving group in the presence ofa suitable base such as cesium carbonate and a suitable solvent such asacetone. Suitable leaving groups include halides such as iodide, andsulfonate esters such as methanesulfonate ester.

Alternatively, a compound of formula of II may be prepared from acompound of formula V (Reaction Scheme A, step c) where R¹² is anappropriate precursor to the group L.

A compound of formula III where R² is halo, phenyl, substituted phenyl,thiophenyl, substituted thiophenyl and the like maybe prepared from acompound of formula VII (Reaction Scheme B). More specifically, acompound of formula VII where X is O is reacted under the appropriatehalogenation conditions to provide a compound of formula III where X isO and R² is a halogen such as chloro, bromo or iodo. A compound offormula III where X is O and R² is a halogen such as chloro, bromo oriodo is reacted with a boronic acid of phenyl, substituted phenyl,thiophenyl, substituted thiophenyl and the like in the presence of atransition metal catalyst such as Pd(dppf)₂Cl₂ and a base such as cesiumhydroxide to provide a compound of formula III where R² is thecorresponding phenyl, substituted phenyl, thiophenyl, substitutedthiophenyl and the like. The reaction is conveniently carried out in asolvent such as solutions of tetrahydrofuran and water.

A compound of formula III where X is S may be prepared from a compoundof formula III where X is O. More specifically, a compound of formulaIII where X is O is reacted with dimethylthiocarbamoyl chloride in asuitable solvent such as dichloromethane. The resulting thiocarbamate isheated in a suitable solvent such as dodecane and treated with sodiumhydroxide to provide a compound of formula III where X is S.

A compound of formula III may also be prepared from a compound offormula IX where the group Pg represents a suitable protecting group(Reaction Scheme C). More specifically in step a, a compound of formulaIX where R² is a halogen such iodo or bromo and Pg is methyl, is reactedwith a boronic acid of phenyl, substituted phenyl, thiophenyl,substituted thiophenyl and the like in the presence of a transitionmetal catalyst such as Pd(dppf)₂Cl₂ and a base such as cesium hydroxideto provide a compound of formula IX where R² is phenyl, substitutedphenyl, thiophenyl, substituted thiophenyl and the like, and Pg ismethyl. The reaction is conveniently carried out in a solvent such as asolution of tetrahydrofuran and water. Further in step a, a compound offormula IX where R² is phenyl, substituted phenyl, thiophenyl,substituted thiophenyl and the like is reacted with an R¹ acyl halidesuch as acetyl chloride and a Lewis acid such as aluminum chloride in asuitable solvent to provide a compound of formula VIII where R¹ ismethyl and R² is phenyl, substituted phenyl, thiophenyl, substitutedthiophenyl and the like. Suitable solvents include dichloromethane. Instep b, a compound of formula VIII where the group Pg is methyl isreacted with deprotection agents such as pyridine hydrochloride in thepresence of microwave radiation to provide a compound of formula IIIwhere R² is phenyl, substituted phenyl, thiophenyl, substitutedthiophenyl and the like.

Additionally in Reaction Scheme C, a compound of formula III where R² isC1-C3 fluoroalkyl may be prepared from a compound of formula IX where R²is a halogen. More specifically, a compound of formula IX where R² isiodo, X is O and Pg is a suitable protecting group such as benzyl isreacted with an alkyl ester of difluoro-fluorosulfonyl-acetic acid inthe presence of hexamethylphosphoramide and a transistion metal catalystsuch as copper iodide in a suitable solvent to provide a compound offormula IX where R² is trifluoromethyl, X is O, and Pg is benzyl.Suitable solvents include dimethylformamide. In step c, a compound offormula IX where R² is trifluoromethyl, X is O, and Pg is benzyl isreacted N-bromosuccinimide in a suitable solvent such asdimethylformamide to provide a compound of formula X. In step d, acompound of formula X is reacted with tributyl-(1-ethoxy-vinyl)-stannaneand a transition metal catalyst such astetrakis(triphenylphosphine)palladium in a solvent such as dioxanefollowed by acid hydrolysis to provide a compound of formula VIII whereR¹ is methyl, R² is trifluoromethyl, X is O, and Pg is benzyl. In stepb, a compound of formula VIII where R¹ is methyl, R² is trifluoromethyl,X is O, and Pg is benzyl is reacted with a transistion metal catalystsuch as palladium hydroxide in the presence of an effective hydrogensource such as cyclohexene to provide a compound of formula III where R¹is methyl, R² is trifluoromethyl, and X is O, Suitable solvents includeethanol.

In Reaction Scheme D, a compound of formula IIa where Pg¹ is a suitablehydroxyl protecting group may be prepared from a compound of formula IVfwhere Pg¹ is the same. More specifically in step a, a compound offormula XVII where Pg is a trialkylsilyl such as tert-butyldimethylsilylis reacted with magnesium in a suitable solvent such as tetrahydrofuran.The resulting Grignard reagent of XVII is reacted with a compound offormula XVIII in a suitable solvent such as tetrahydrofuran to provide acompound of formula XIX where Pg is tert-butyldimethylsilyl and R¹⁰ is asuitable precursor to Z such as cyano.

In step b, a compound of formula XIX where Pg is tert-butyldimethylsilylis reacted with a second protecting agent such as 3,4-dihydro-2H-pyranand a suitable catalyst such as pyridinium-para-toluenesulfonate toprovide a compound of formula XIXa where Pg is tert-butyldimethylsilyland Pg¹ is tetrahydro-2H-pyran. The reaction is conveniently carried outin a solvent such as dichloromethane. Additional second protectingagents such as acetic acid anhydride in the presence of a base such astriethylamine may be used to provide a compound of formula XIXa where Pgis tert-butyldimethylsilyl and Pg¹ is acetyl. In step c, a compound offormula XIXa is reacted with an agent that removes protecting group Pgwithout removing protecting group Pg¹. More specifically in step c, acompound of formula XIXa where Pg is tert-butyldimethylsilyl and Pg¹ istetrahydro-2H-pyran is reacted with tetrabutylammonium fluoride in asuitable solvent such as tetrahydrofuran to provide a compound offormula IVf where Pg¹ is tetrahydro-2H-pyran. Alternatively, a compoundof formula XIXa where Pg is tert-butyldimethylsilyl and Pg¹ is acetyl isreacted with an acid such as hydrochloric acid at about room temperatureto provide a compound of formula IVf where Pg¹ is acetyl.

In Reaction Scheme E, compounds of formula Ia and Ib may be preparedfrom a compound of formula Ia where Pg¹ represents a suitable protectinggroup. More specifically in step a, a compound of formula Ia where R¹⁰is a suitable precursor to Z such as nitrile is reacted with an azidesource such as sodium azide in the presence of a suitable Lewis acidsuch as zinc bromide to provide a compound of formula Ia where Z istetrazolyl. The reaction is conveniently carried out in a solvent suchas water and isopropyl alcohol. In step b, a compound of formula Ia isreacted with reducing agents such as triethylsilane in the presence of asuitable Lewis acid such as boron trifluoride diethyl etherate toprovide a compound of formula Ib where Z is tetrazolyl. The reaction isconveniently carried out in a solvent such as dichloromethane.

In Reaction Scheme F, compounds of IIc and IId may be prepared from acompound of formula IIa where Pg¹ is a suitable protecting group. Morespecifically in step a, a compound of formula Ia is reacted with asuitable acid such as p-toluenesulfonic acid to provide a compound offormula IIb. The reaction is conveniently carried out in a solvent suchas methanol. In step b, a compound of formula IIb is reacted with ahalogenating agent such as diethylaminosulfur trifluoride

in a solvent such as dichloromethane to provide a compound of formulaIIc. In step c, a compound of formula IIb is reacted with an oxidizingagent such as Dess-Martin periodinane(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (H)-one) in a suitablesolvent such as dichloromethane to provide a compound of formula IId.

In Reaction Scheme G, a compound of IIf where R² is phenyl, substitutedphenyl, thiophenyl, substituted thiophenyl, thiazolyl, substitutedthiazolyl, furanyl, substituted furanyl, pyridinyl, substitutedpyridinyl, oxazolyl, substituted oxazolyl, isothiazolyl, substitutedisothiazolyl, isoxazolyl, substituted isoxazolyl, 1,2,4-oxadiazolyl,pyrimidinyl, substituted pyrimidinyl or substituted 1,2,4-oxadiazolylmay be prepared from a compound where R² is a suitable coupling groupsuch as the halogen iodo. More specifically in step a, a compound offormula XXI where R¹⁴ is a suitable coupling group such as the halogenbromo is reacted with a compound of formula XX in the presence of asuitable transition metal catalyst such as tetrakistriphenylphosphinepalladium(0) and a suitable base such as aqueous sodium carbonate toprovide a compound of formula Ivg where R¹¹ is hydroxyl. The reaction isconveniently carried out in a solvent such as toluene. In step b, acompound of formula IVg where R¹¹ is a suitable coupling group such ashydroxyl or the halogen iodo is reacted with a compound of formula IIIa,as described in Scheme A for a compound of formula II, to provide acompound of formula IIe.

In step c, a compound of formula IIe is reacted with a trialkylstannanylderivative of phenyl, substituted phenyl, thiophenyl, substitutedthiophenyl, thiazolyl, substituted thiazolyl, furanyl, substitutedfuranyl, pyridinyl, substituted pyridinyl, oxazolyl, substitutedoxazolyl, isothiazolyl, substituted isothiazolyl, isoxazolyl,substituted isoxazolyl, 1,2,4-oxadiazolyl, pyrimidinyl, substitutedpyrimidinyl or substituted 1,2,4-oxadiazolyl in the presence of asuitable transition metal catalyst such as tetrakistriphenylphosphinepalladium (0) to provide a compound of formula IIf where R² is phenyl,substituted phenyl, thiophenyl, substituted thiophenyl, thiazolyl,substituted thiazolyl, furanyl, substituted furanyl, pyridinyl,substituted pyridinyl, oxazolyl, substituted oxazolyl, isothiazolyl,substituted isothiazolyl, isoxazolyl, substituted isoxazolyl,1,2,4-oxadiazolyl, pyrimidinyl, substituted pyrimidinyl or substituted1,2,4-oxadiazolyl. The reaction is conveniently carried out in a solventsuch as toluene.

In Reaction Scheme H, a compound of formula IVh where Ar₁ is aheterocyclic ring such as 1,2,4-oxadiazol-3,5-diyl may be prepared bycondensing two heterocyclic precursors. More specifically in step a, achloroacetic anhydride of formula XXII is reacted with anN-hydroxyphenylacetamide of formula XXIII under conditions of waterremoval to provide a compound of formula IVh where Ar₁ is1,2,4-oxadiazol-3,5-diyl. The reaction is conveniently carried out in asolvent such as toluene. Compound IVh may then be coupled to a compoundof formula III as described in step b of Scheme A to provide a compoundof formula IIg where Ar₁ is a heterocyclic ring such as1,2,4-oxadiazol-3,5-diyl and R¹⁰ is a halogen such as an iodide. Acompound of formula IIg where Ar₁ is a heterocyclic ring such as1,2,4-oxadiazol-3,5-diyl and R¹⁰ is iodide may then be transformed intoa compound of formula I where Ar₁ is a heterocyclic ring such as1,2,4-oxadiazol-3,5-diyl and Z is a carboxylic acid throughcarbonylation with an appropriate transistion metal catalyst such as(CH₃CN)₂PdCl₂ in the presence of carbon monoxide. An appropriate solventfor this transformation is water.

In Reaction Scheme I, a compound of formula XXVII where Ar₁ is aheterocyclic ring such as 1,2,4-oxadiazol-3,5-diyl may be prepared bycondensing two heterocyclic precursors. More specifically, a carboxylicacid of formula XXV is reacted with an appropriately substitutedN-hydroxyacetamide of formula XXVI under conditions of water removal asshown in step a to provide a compound of formula XXVII where Ar₁ is the1,2,4-oxadiazol-3,5-diyl. Compound XXVII (R¹¹ ═OPg) may then betransformed into a compound of formula XXVII where R¹¹ is a hydroxyl andcoupled to a compound of formula III as described in step b of Scheme Ato provide a compound of formula IIh where Ar₁ is a heterocyclic ringsuch as 1,2,4-oxadiazol-3,5-diyl and R¹⁰ is an ester.

In Reaction Scheme J, step c, an enantomeric compound of formula XIXbmay prepared by resolution of a racemic compound of formula XIX byconventionally procedures including chromatographic separation using achiral stationary phase. Alternatively, in step b, an enantomericcompound of formula XIXb may be prepared by arylating enantioselectivelya compound of formula of XVIII with a compound of formula XXX. Morespecifically, in step a, a compound of formula XVII where Pg is anhydroxyl protecting group such as tert-butyldimethylsilyl is reactedunder borating conditions in which the borating conditions comprise atriakyl borate such as triisopropyl borate and an alkyl lithium such asn-hexyllithium to provide a borate trimer of formula XXX. The reactionis conveniently carried out in a suitable solvent such as toluene. Alsocontemplated within the scope of a compound of formula XXX are thecorresponding dimer and monomer forms of the aryl boronic acid. In stepb, an enantiomeric compound of formula XIXb is prepared by arylating analdehyde of formula XVIII with a borate trimer of formula XXX in thepresence of a chiral catalyst and a dialkyl zinc. More specifically, acompound of formula XXX is reacted with a dialkyl zinc for 12 to 18hours in a suitable solvent such as toluene at a temperature from 20° C.to 80° C. A temperature of 40° C. to 80° C. is preferred with 60° C.being more preferred. Dialkyl zincs such as dimethyl zinc anddiisopropyl zinc are preferred with diethyl zinc being more preferred.Following the reaction with a dialkyl zinc, the reaction is cooled to10° C. to −20° C. with −10° C. being preferred and a chiral catalyst,preferably in a suitable solvent such as toluene, is added. Preferredchiral catalysts include chiral amino alcohols such as1-[(R)-[methyl[(1R)-1-phenylethyl]amino]-1-naphthalenylmethyl]-2-naphthalenol,[(S)-1-naphthalenyl[[(1S)-1-phenylethyl]amino]methyl]-2-naphthalenol and[(S)-[methyl[(1S)-1-phenylethyl]amino]phenylmethyl]-2-naphthalenol with(R)-(−)-2-piperidino-1,1,2-triphenyl ethanol being more preferred. Thereaction maintained for 15 to 90 minutes with 30 minutes beingpreferred. A compound of formula XVIII where R¹⁰ is cyano is added andthe reaction is maintained for 2 to 6 hours with 4 hours beingpreferred. The reaction is quenched and subject to standard extractiontechniques to provide an enantomeric compound of formula XIXb where Pgis a hydroxyl protecting group such as tert-butyldimethylsilyl and R¹⁰is a suitable precursor to the group Z such as cyano.

The compounds of the present invention can be administered alone or inthe form of a pharmaceutical composition, that is, combined withpharmaceutically acceptable carriers or excipients, the proportion andnature of which are determined by the solubility and chemical propertiesof the compound selected, the chosen route of administration, andstandard pharmaceutical practice. The compounds of the presentinvention, while effective themselves, may be formulated andadministered in the form of their pharmaceutically acceptable salts, forpurposes of stability, convenience of crystallization, increasedsolubility, and the like.

In practice, the compounds of formula I are usually administered in theform of pharmaceutical compositions, that is, in admixture withpharmaceutically acceptable carriers or diluents, the proportion andnature of which are determined by the chemical properties of theselected compound of formula I, the chosen route of administration, andstandard pharmaceutical practice.

Thus, the present invention provides pharmaceutical compositionscomprising a compound of the formula I and a pharmaceutically acceptablecarrier, diluent or excipient.

The compounds of formula I can be administered by a variety of routes.In effecting treatment of a patient afflicted with disorders describedabove, a compound of formula I can be administered in any form or modewhich makes the compound bioavailable in an effective amount, includingoral and parenteral routes. For example, compounds of formula I can beadministered orally, by inhalation, subcutaneously, intramuscularly,intravenously, transdermally, intranasally, rectally, ocularly,topically, sublingually, buccally, and the like. Oral administration isgenerally preferred for treatment of the neurological and psychiatricdisorders described herein.

One skilled in the art of preparing formulations can readily select theproper form and mode of administration depending upon the particularcharacteristics of the compound selected, the disorder or condition tobe treated, the stage of the disorder or condition, and other relevantcircumstances. (Remington's Pharmaceutical Sciences, 18th Edition, MackPublishing Co. (1990)).

The pharmaceutical compositions of the present invention are prepared ina manner well known in the pharmaceutical art. The carrier or excipientmay be a solid, semi-solid, or liquid material which can serve as avehicle or medium for the active ingredient. Suitable carriers orexcipients are well known in the art. The pharmaceutical composition maybe adapted for oral, inhalation, parenteral, or topical use and may beadministered to the patient in the form of tablets, capsules, aerosols,inhalants, suppositories, solution, suspensions, or the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or capsules or compressed into tablets.For the purpose of oral therapeutic administration, the compounds may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gums and thelike. These preparations should contain at least 4% of the compound ofthe present invention, the active ingredient, but may be varieddepending upon the particular form and may conveniently be between 4% toabout 70% of the weight of the unit. The amount of the compound presentin compositions is such that a suitable dosage will be obtained. Aperson skilled in the art may determine preferred compositions andpreparations according to the present invention.

The tablets, pills, capsules, troches, and the like may also contain oneor more of the following adjuvants: binders such as microcrystallinecellulose, gum tragacanth or gelatin; excipients such as starch orlactose, disintegrating agents such as alginic acid, Primogel, cornstarch and the like; lubricants such as magnesium stearate or Sterotex;glidants such as colloidal silicon dioxide; and sweetening agents suchas sucrose or saccharin may be added or a flavoring agent such aspeppermint, methyl salicylate or orange flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol or a fatty oil. Otherdosage unit forms may contain other various materials which modify thephysical form of the dosage unit, for example, as coatings. Thus,tablets or pills may be coated with sugar, shellac, or other coatingagents. A syrup may contain, in addition to the present compounds,sucrose as a sweetening agent and certain preservatives, dyes andcolorings and flavors. Materials used in preparing these variouscompositions should be pharmaceutically pure and non-toxic in theamounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations typically contain at least 0.1% of acompound of the invention, but may be varied to be between 0.1 and about90% of the weight thereof. The amount of the compound of formula Ipresent in such compositions is such that a suitable dosage will beobtained. The solutions or suspensions may also include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl paraben; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylene diaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic. Preferred compositionsand preparations are able to be determined by one skilled in the art.

The compounds of the present invention may also be administeredtopically, and when done so the carrier may suitably comprise asolution, ointment, or gel base. The base, for example, may comprise oneor more of the following: petrolatum, lanolin, polyethylene glycols,bees wax, mineral oil, diluents such as water and alcohol, andemulsifiers, and stabilizers. Topical formulations may contain aconcentration of the formula I or its pharmaceutical salt from about 0.1to about 10% w/v (weight per unit volume).

The compounds of formula I are potentiators of metabotropic glutamate(mGlu) receptor function, in particular they are potentiators of mGlu2receptors. That is the compounds of formula I increase mGlu2 receptorresponse to glutamate or a glutamate agonist, enhancing the function ofthe receptors. The behavior of the potentiators of formula I at mGlu2receptors is shown in Example A which is suitable to identifypotentiators useful for carrying out the present invention. Thus, thepotentiators of the present invention are expected to be useful in thetreatment of various neurological and psychiatric disorders associatedwith glutamate dysfunction described to be treated herein and othersthat can be treated by such potentiators as are appreciated by thoseskilled in the art.

Example A Potentiation of Glutamate-Induced Increase in IntracellularCalcium with a mGlu2 Expressing Cell Line

Cell lines expressing human mGlu2 receptors are derived as previouslydescribed (Desai, Burnett, Mayne, Schoepp, Mol. Pharmacol. 48, 648-657,1995) and cultured in DMEM with 5% dialyzed fetal bovine serum, 1 mMglutamine, 1 mM sodium pyruvate, 50 μg/mL Geneticin G418, and 0.2 mg/mLhygromycin B. Confluent cultures are passaged weekly. These cells arereferred to as RGT cells for Rat Glutamate Transporter, and have beenco-transfected with the glutamate/aspartate transporter GLAST. The RGTcell line expressing the mGlu2 receptors is stably transfected with thepromiscuous G-protein, Galpha15 to change the signaling pathway to themGlu2 receptor to one that could be easily measured through release ofintracellular calcium. Thus, intracellular calcium levels are monitoredbefore and after the addition of drugs on a Fluorometric Imaging PlateReader (i.e. FLIPR, Molecular Devices). The following buffer is usedthroughout as an assay buffer: 10 mM KCl, 138 mM NaCl, 5 mM Ca Cl₂, 1 mMMgCl₂, 4 mM Na H₂PO₄, 10 mM Glucose, 10 mM HEPES, pH 7.4. Cells that hadbeen plated 48 hours prior at a density of 30-40,000 cells per well in a96-well plate are loaded with a calcium-sensitive dye for 90 minutes at25° C. Fluo-3 (2 mM in DMSO, Molecular Probes) are mixed with a equalvolume of 10% pluronic acid in DMSO, and diluted to 8 μM into the bufferdescribed above containing 10% fetal bovine serum to make the loadingbuffer. Following loading of the cells, the loading buffer is removedand replaced with assay buffer prior to drug addition and monitoring onthe FLIPR. The resulting signal from the addition of compounds offormula (I) and submaximal concentrations of a glutamate-site agonist(e.g. 1 μM glutamate) is determined by taking the difference of themaximal fluorescent peak height minus the background fluorescence ineach well and expressing the results as a percent of the signal seenwith a maximal glutamate response (30 μM glutamate, typically about30-50,000 Relative Fluorescent Units). Least squares curve fitting witha four-parameter equation is then applied to the resulting dose-%response curve to determine the resulting EC50 values.

Exemplified compounds of formula I typically affect the potentiation ofmGlu2 receptors with EC50 values less than 12.5 μM. More specifically,examples 47, 65, 81, 82, 83 and 84 affect the potentiation of mGlu2receptors with EC50 values less than 100 nM.

Compounds of formula I are modulators of leukotriene receptor function,in particular they are antagonists of leukotriene receptors. That is thecompounds of formula I antagonize the cysteinyl-leukotriene D4 (LTD4)receptor. The behavior of the antagonism of the cysteinyl-leukotriene D4(LTD4) receptor by compounds of formula I is shown in Example B which issuitable to identify antagonists useful for carrying out the presentinvention. Thus, the leukotriene antagonists of the present inventionare useful in the treatment of various inflammatory and allergicdisorders mediated by leukotrienes and described to be treated hereinand other disorders that can be treated by such antagonists as areappreciated by those skilled in the art.

Example B Antagonism of Cysteinyl-leukotriene D4 (LTD4)-Induced Increasein Intracellular Calcium within a Cysteinyl-Leukotriene 1 (CysLT1)Receptor Expressing Cell Line

Cell lines expressing the human CysLT1 receptor [AV12-664 (ATCC-9595)]are derived and maintained in culture media: DMEM with 5% dialyzed fetalbovine serum, 1 mM glutamine, and 1 mM sodium pyruvate. Confluentcultures are passaged weekly. Intracellular calcium levels are monitoredin the CysLT1-expressing cells with the addition of LTD4, with orwithout prior exposure to the compounds being tested as antagonists witha Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices). Thefollowing buffer is used throughout as an assay buffer: Hanks BufferedSaline Solution without phenol red (GIBCO), with 10 mM HEPES pH 7.4.Cells that had been plated 48 hours prior at a density of 20-25,000cells per well in a 96-well plate are loaded with a calcium-sensitivedye for 90 minutes at 25° C. Fluo-3 (2 mM in DMSO, Molecular Probes) ismixed with an equal volume of 10% pluronic acid in DMSO, and diluted to8 μM in the buffer described above containing 10% fetal bovine serum tomake the loading buffer. Following loading of the cells, the buffer isremoved and replaced with assay buffer prior to drug addition andmonitoring on the FLIPR for several minutes. The resulting signal fromthe addition of 6 nM LTD4 (provides approximately 90% of the maximalsignal with 25 nM LTD4) is determined by taking the difference of themaximal fluorescent peak height minus the background fluorescence ineach well and expressing the results as a percent of the signal seenwithout pretreatment of the test compound(s). Least squares curvefitting with a four-parameter equation is applied to the resultingdose-% inhibition curve to determine the resulting IC50 values.

Exemplified compounds of formula I typically affect the antagonism ofCysLT1 receptors with IC50 values less than 12.5 μM. More specifically,examples 47, 60, 65, 81, 82, 83 and 84 affect the antagonism of CysLT1receptors with IC50 values less than 750 nM.

In one embodiment of the present invention provides methods of treatingneurological and psychiatric disorders associated with glutamatedysfunction, comprising administering to a patient in need thereof aneffective amount of a potentiator of metabotropic glutamate 2 receptors.

Specifically, the present invention provides a method of treatingneurological and psychiatric disorders associated with glutamatedysfunction, comprising administering to a patient in need thereof aneffective amount of a potentiator of the mGlu2 receptor and/orantagonist of the CysLT1 receptor, that is, the present inventionprovides methods using an effective amount of a potentiator of mGlu2receptors and/or antagonist of the CysLT1 receptor.

In another preferred embodiment the present invention provides a methodof treating migraine, comprising administering to a patient in needthereof an effective amount of a compound of formula I.

In another preferred embodiment the present invention provides a methodof treating anxiety, comprising administering to a patient in needthereof an effective amount of a compound of formula I.

Particularly preferred anxiety disorders are generalized anxietydisorder, panic disorder, and obsessive compulsive disorder.

In another preferred embodiment the present invention provides a methodof treating schizophrenia, comprising administering to a patient in needthereof an effective amount of a compound of formula I.

In yet another preferred embodiment the present invention provides amethod of treating epilepsy, comprising administering to a patient inneed thereof an effective amount of a compound of formula I.

Because the compounds of formula I enhance the normal physiologicalfunction of the mGlu receptors, the compounds of formula I are usefulfor the treatment of a variety of neurological and psychiatric disordersassociated with glutamate dysfunction, including: acute neurological andpsychiatric disorders such as cerebral deficits subsequent to cardiacbypass surgery and grafting, stroke, cerebral ischemia, spinal cordtrauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemicneuronal damage, dementia (including AIDS-induced dementia), Alzheimer'sdisease, Huntington's Chorea, amyotrophic lateral sclerosis, multiplesclerosis, ocular damage, retinopathy, cognitive disorders, idiopathicand drug-induced Parkinson's disease, muscular spasms and disordersassociated with muscular spasticity (including tremors) seizures,epilepsy, convulsions, migraine (including migraine headache), urinaryincontinence, substance tolerance, substance withdrawal (including,substances such as opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis,schizophrenia, anxiety (including generalized anxiety disorder, panicdisorder, and obsessive compulsive disorder), mood disorders (includingdepression, mania, bipolar disorders), trigeminal neuralgia, hearingloss, tinnitus, macular degeneration of the eye, emesis, brain edema,pain (including acute and chronic pain states, severe pain, intractablepain, neuropathic pain, and post-traumatic pain), tardive dyskinesia,sleep disorders (including narcolepsy), attention deficit/hyperactivitydisorder, and conduct disorder.

At present, the fourth edition of the Diagnostic and Statistical Manualof Mental Disorders (DSM-IV™) (1994, American Psychiatric Association,Washington, D.C.), provides a diagnostic tool for identifying many ofthe disorders described herein. The skilled artisan will recognize thatthere are alternative nomenclatures, nosologies, and classificationsystems for neurological and psychiatric disorders described herein andthat these systems evolve with medical scientific progress.

The compounds of formula I potentiate mGlu receptor response, inparticular mGlu2 receptor response, to glutamate and glutamate agonists.Such agonists are easily recognized and some are available in the art.Schoepp, D. D., Jane, D. E., Monn, J. A., Neuropharmacology 38:1431-1476, (1999).

Thus, a more particular embodiment, it is understood that the presentinvention extends to a method of potentiating the action of a glutamatereceptor agonist at the Group II mGlu receptors, comprisingadministering to a patient in need thereof an effective amount of amGlu2 potentiator, in particular a compound of formula I, in combinationwith a potentiated amount of an mGlu receptor agonist. Such acombination may be advantageous in that it may augment the activity andselectivity of mGlu agonist.

As used herein, the term “patient” refers to a warm blooded animal suchas a mammal which is afflicted with one or more neurological andpsychiatric disorders associated with glutamate dysfunction. It isunderstood that guinea pigs, dogs, cats, rats, mice, horses, cattle,sheep, and humans, particularly humans, are examples of animals withinthe scope of the meaning of the term. It is also understood that thisinvention relates specifically to the potentiation of mammalianmetabotropic glutamate receptors.

It is also recognized that one skilled in the art may affect theneurological and psychiatric disorders by treating a patient presentlyafflicted with the disorders or by prophylactically treating a patientafflicted with the disorders with an effective amount of the compound offormula I. Thus, the terms “treatment” and “treating” are intended torefer to all processes wherein there may be a slowing, interrupting,arresting, controlling, or stopping of the progression of theneurological and psychiatric disorders described herein, but does notnecessarily indicate a total elimination of all disorder symptoms, andis intended to include prophylactic treatment of such neurological andpsychiatric disorders.

As used herein, the term “effective amount” of a compound of formula Irefers to an amount, that is, the dosage which is effective in treatingthe neurological and psychiatric disorders described herein.

The attending diagnostician, as one skilled in the art, can readilydetermine an effective amount by the use of conventional techniques andby observing results obtained under analogous circumstances. Indetermining an effective amount, the dose of a compound of formula I, anumber of factors are considered by the attending diagnostician,including, but not limited to: the compound of formula I to beadministered; the co-administration of an mGlu agonist, if used; thespecies of mammal; its size, age, and general health; the specificdisorder involved; the degree of involvement or the severity of thedisorder; the response of the individual patient; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the use of other concomitantmedication; and other relevant circumstances.

An effective amount of a compound of formula I is expected to vary fromabout 0.01 milligram per kilogram of body weight per day (mg/kg/day) toabout 100 mg/kg/day. Preferred amounts may be determined by one skilledin the art.

As used herein, the term “potentiated amount” refers to an amount of anmGlu agonist, that is, the dosage of agonist which is effective intreating the neurological and psychiatric disorders described hereinwhen administered in combination with an effective amount of a compoundof formula I. A potentiated amount is expected to be less than theamount that is required to provided the same effect when the mGluagonist is administered without an effective amount of a compound offormula I.

The attending diagnostician, as one skilled in the art, can readilydetermine a potentiated amount by the use of conventional techniques andby observing results obtained under analogous circumstances. Indetermining a potentiated amount, the dose of an mGlu agonist to beadministered in combination with a compound of formula I, a number offactors are considered by the attending diagnostician, including, butnot limited to: the mGlu agonist selected to be administered, includingits potency and selectivity; the compound of formula I to beco-administered; the species of mammal; its size, age, and generalhealth; the specific disorder involved; the degree of involvement or theseverity of the disorder; the response of the individual patient; themodes of administration; the bioavailability characteristics of thepreparations administered; the dose regimens selected; the use of otherconcomitant medication; and other relevant circumstances.

A potentiated amount of an mGlu agonist to be administered incombination with an effective amount of a compound of formula I isexpected to vary from about 0.1 milligram per kilogram of body weightper day (mg/kg/day) to about 100 mg/kg/day and is expected to be lessthan the amount that is required to provided the same effect whenadministered without an effective amount of a compound of formula I.Preferred amounts of a co-administered mGlu agonist are able to bedetermined by one skilled in the art.

Of the neurological and psychiatric disorders associated with glutamatedysfunction which are treated according to the present invention, thetreatment of migraine, anxiety, schizophrenia, and epilepsy areparticularly preferred. Particularly preferred anxiety disorders aregeneralized anxiety disorder, panic disorder, and obsessive compulsivedisorder.

Thus, in a preferred embodiment the present invention provides a methodof treating migraine, comprising administering to a patient in needthereof an effective amount of a compound of formula I or apharmaceutical composition thereof.

In one of the available sources of diagnostic tools, Dorland's MedicalDictionary (23^(rd) Ed., 1982, W. B. Saunders Company, Philadelphia,Pa.), migraine is defined as a symptom complex of periodic headaches,usually temporal and unilateral, often with irritability, nausea,vomiting, constipation or diarrhea, and photophobia. As used herein theterm “migraine” includes these periodic headaches, both temporal andunilateral, the associated irritability, nausea, vomiting, constipationor diarrhea, photophobia, and other associated symptoms. The skilledartisan will recognize that there are alternative nomenclatures,nosologies, and classification systems for neurological and psychiatricdisorders, including migraine, and that these systems evolve withmedical scientific progress.

In another preferred embodiment the present invention provides a methodof treating anxiety, comprising administering to a patient in needthereof an effective amount of a compound of formula I or apharmaceutical composition thereof.

At present, the fourth edition of the Diagnostic and Statistical Manualof Mental Disorders (DSM-IV™) (1994, American Psychiatric Association,Washington, D.C.), provides a diagnostic tool including anxiety andrelated disorders. These include: panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobia, social phobia, obsessive-compulsive disorder, post-traumaticstress disorder, acute stress disorder, generalized anxiety disorder,anxiety disorder due to a general medical condition, substance-inducedanxiety disorder and anxiety disorder not otherwise specified. As usedherein the term “anxiety” includes treatment of those anxiety disordersand related disorder as described in the DSM-IV. The skilled artisanwill recognize that there are alternative nomenclatures, nosologies, andclassification systems for neurological and psychiatric disorders, andparticular anxiety, and that these systems evolve with medicalscientific progress. Thus, the term “anxiety” is intended to includelike disorders that are described in other diagnostic sources.

A number of preclinical laboratory animal models for migraine andanxiety have been described. One commonly used model of migraine is thedural extravasation model that has been described by Phebus et al., LifeSci., 61(21), 2117-2126 (1997) which can be used to evaluate the presentcompounds.

Example C Animal Model of Dural Plasma Protein Extravasation (PPE)

Male Harlan Sprague-Dawley rats (250-350 g) are anesthetized with sodiumpentobarbital (65 mg/kg, i.p.) and placed in a stereotaxic frame (DavidKopf Instruments) with the incisor bar set at −2.5 mm. Following amidline sagital scalp incision, two pairs of bilateral holes are drilledthrough the skull (3.2 mm posterially, 1.8 and 3.8 mm laterally, allcoordinates referenced to bregma). Pairs of stainless steel stimulatingelectrodes, insulated except at the tips (Rhodes Medical Systems, Inc.),are lowered through the holes in both hemispheres to a depth of 9.2 mm.

The femoral vein is exposed and a dose of the test compound is injectedintravenously (i.v.) at a dosing volume of 1 mL/kg. Approximately 8minutes post i.v. injection, a 20 mg/kg dose of Fluoresceinisothiocyanate-bovine serum albumin (FITC-BSA) is also injectedintravenously. The FITC-BSA functions as a marker for proteinextravasation. Exactly 10 minutes post-injection of the test compound,the left trigeminal ganglion is stimulated for 5 minutes at a currentintensity of 1.0 mA (5 Hz, 5 msec duration) with a Model S48 GrassInstrument Stimulator with PSIU6 photoelectric isolation unit(Grass-Telefactor).

Alternatively, rats fasted overnight are dosed orally with test compoundvia gavage at a volume of 2 mL/kg. Approximately 50 minutes later theanimals are anesthetized and placed in the stereotaxic frame asdescribed above. Exactly 58 minutes post-p.o. dosing, the animals aredosed with FITC-BSA (20 mg/kg, i.v.). Exactly one hour post-p.o. dosing,the animals are stimulated as described above.

Five minutes following stimulation, the animals are killed byexsanguination with 40 mL of saline. The top of the skull is removed tofacilitate the collection of the dural membranes. The membrane samplesare removed from both hemispheres, rinsed with water, and spread flat onmicroscopic slides. Once dried, the tissues are coverslipped with a 70%glycerol/water solution.

A fluorescence microscope (Zeiss) equipped with a grating monochromatorand a spectrophotometer is used to quantify the amount of FITC-BSA ineach sample. An excitation wavelength of approximately 490 nm isutilized and the emission intensity at 535 nm was determined. Themicroscope is equipped with a motorized stage and also interfaced with apersonal computer. This facilitates the computer-controlled movement ofthe stage with fluorescence measurements at 25 points (500 mm steps) oneach dural sample. The mean and standard deviation of the measurementsare determined by the computer.

The extravasation induced by the electrical stimulation of thetrigeminal ganglion is an ipsilateral effect (i.e. occurs only on theside of the dura in which the trigeminal ganglion was stimulated). Thisallows the use of the other (unstimulated) half of the dura as acontrol. The ratio of the amount of extravasation in the dura from thestimulated side, over the amount of extravasation in the unstimulatedside, is calculated. Control animals dosed only with saline, yield aratio of approximately 2.0. In contrast, a compound which effectivelyprevented the extravasation in the dura from the stimulated side wouldyield a ratio of approximately 1.0.

Examples 60, 65, 83 and 84 affect extravasation in the dura with ID₁₀₀values less than or equal to 0.1 mg/kg p.o.

The fear potentiated startle response model has been extensively used asa model of anxiety and can be used to evaluate the present compounds.Davis, Psychopharmacol., 62, 1 (1979); Davis, Behav. Neurosci., 100, 814(1986); Davis, Tr. Pharmacol. Sci., 13, 35 (1992).

Example D Fear Potentiated Startle Paradigm

Male Sprague-Dawley rats weighing 325-400 g are purchased from HarlanSprague-Dawley, Inc. (Cumberland, Ind.) and given a one week acclimationperiod before testing. Rats are individually housed with food and waterad libitum in an animal room on a 12-hour light/dark cycle with lightson between 6:00 A.M. and 6:00 P.M. The test compound of formula I isprepared in a suspension of 5% ethanol, 0.5% CMC, 0.5% Tween 80 and 99%water. 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)propionic acid is prepared in sterile water. Control rats are given therespective vehicle.

The fear potentiated startle paradigm is conducted over threeconsecutive days. All three days begin with a 5-minute adaptation periodbefore the trial starts. On day one (baseline startle) after theadaptation period, the animal receives 30 trials of 120 dB auditorynoise. The mean startle amplitude (V_(max)) is used to assign animals togroups with similar means before conditioning begins. Day two consistsof conditioning the animals. Each animal receives 0.5 mA of shock for500 msec preceded by a 5 second presentation of light which remains onfor the duration of the shock. Ten presentations of the light and shockare administered. Day three is the testing trial where drugadministration occurs prior to testing. Twenty-four hours afterconditioning, startle testing sessions are conducted. Ten trials ofacoustic startle (120 dB), non-light paired, are presented at thebeginning of the session. This is followed by 20 random trials of thenoise alone and 20 random trials of noise preceded by light. Excludingthe first 10 trials, the startle response amplitudes for each trial typeare averaged for each animal. Data is presented as the differencebetween light+noise and noise-alone. Differences in startle responseamplitudes are analyzed by JMP statistical software using a One-wayAnova (analysis of variance, t-test). Group differences are consideredto be significant at p<0.05.

In another preferred embodiment the present invention provides a methodof treating epilepsy, comprising administering to a patient in needthereof an effective amount of a compound of formula I or apharmaceutical composition thereof.

At present, there are several types and subtypes of seizures associatedwith epilepsy, including idiopathic, symptomatic, and cryptogenic. Theseepileptic seizures can be focal (partial) or generalized. They can alsobe simple or complex. Epilepsy is described in the art, such asEpilepsy: A comprehensive textbook. Ed. by Jerome Engel, Jr. and TimothyA. Pedley. (Lippincott-Raven, Philadelphia, 1997). At present, theInternational Classification of Diseases, Ninth Revision, (ICD-9)provides a diagnostic tool including epilepsy and related disorders.These include: generalized nonconvulsive epilepsy, generalizedconvulsive epilepsy, petit mal status epilepticus, grand mal statusepilepticus, partial epilepsy with impairment of consciousness, partialepilepsy without impairment of consciousness, infantile spasms, epilepsypartialis continua, other forms of epilepsy, epilepsy, unspecified, NOS.As used herein the term “epilepsy” includes these all types andsubtypes. The skilled artisan will recognize that there are alternativenomenclatures, nosologies, and classification systems for neurologicaland psychiatric disorders, including epilepsy, and that these systemsevolve with medical scientific progress.

Various electroshock-induces models has been extensively used as a modelof seizure disorders.

Example E Electroshock-Induced Seizures

Application of electrical stimulation by corneal electrodes to mice caninduce tonic hindlimb-extensor seizures. Blockade of tonic extensorseizures induced by electroshock is considered predictive for drugswhich block seizure propagation and may be effective in preventingvarious seizures in humans, including epileptic seizures.

Vehicle or a dose of a test drug are administered to groups of 5 to 10mice each. Thirty minutes later, electroshock (10 mA, 0.2 sec duration)is administered by transcorneal electrodes. The number of miceexhibiting tonic extensor seizures in each group is recorded. The dataare reported as the percentage of mice that are protected from seizures.

The present invention is further illustrated by the following examplesand preparations. These examples and preparations are illustrative onlyand are not intended to limit the invention in any way.

The chemical nomenclature used in the examples and preparations isderived from one or more standard conventions. The skilled artisan willrecognize the technical meaning when names are derived from two or moreconventions.

The terms used in the examples and preparations have their normalmeanings unless otherwise designated. For example, “° C.” refers todegrees Celsius; “N” refers to normal or normality; “M” refers to molaror molarity; “mol” refers to mole or moles; “mmol” refers to millimoleor millimoles; “mmol” refers to micromole or micromoles; “kg” refers tokilogram or kilograms; “g” refers to gram or grams; “mg” refers tomicrogram or micrograms; “mg” refers to milligram or milligrams; “mL”refers to microliter or microliters; “mL” refers milliliter ormilliliters; “L” refers to liter or liters; “bp” refers to boilingpoint; “mp” refers to melting point; “brine” refers to a saturatedaqueous sodium chloride solution; “h or hr” refers to hour or hours;“min” refers to minute or minutes; “MS” refers to mass spectrometry;“NMR” refers to nuclear magnetic resonance spectroscopy; “TFA” refers totrifluoroacetic acid; “CH₂Cl₂” or “DCM” refers to dichloromethane; “DCE”refers to dichloroethane; “MeOH” refers to methanol; “NH₄OH” refers to aconcentrated aqueous ammonia solution; “HCl” refers to hydrogenchloride; “MTBE” refers to tert-butyl methyl ether; “DSC” refers todifferential scanning calorimetery; “DMEM” refers to Dulbecco's modifiedeagle medium. Chemical shifts are give in δ and NMR spectra wereobtained in CDC₁₃, unless otherwise indicated.

Preparation 1 Synthesis of 2-fluoro-3-methoxy-phenol

A mixture of 2-fluoroanisole (1.8 ml, 15.85 mmol),pentamethyldiethyenetriamine (3.6 mL, 17.45 mmol) and tetrahydrofuran(10 mL) is stirred at −78° C. A 2.5 M solution of n-butyllithium inhexanes (7 ml, 17.45 mmol) is added dropwise and the resulting solutionis stirred at −78° C. 2 hr. Trimethylborate (2 mL, 17.45 mmol) is addedand the reaction is warmed to room temperature and stirred 1 hr. Aceticacid (1.4 ml, 23.8 mmol) is added followed by an aqueous 30% solution ofhydrogen peroxide (1.8 mL, 17.45 mmol) and the resulting mixture isstirred rapidly 18 hr at room temperature. The reaction mixture isdiluted with water and extracted with ethyl acetate (3×50 mL). Thecombined extracts are dried over magnesium sulfate, filtered andconcentrated to about 10 mL volume. The resulting mixture is purifiedvia silica chromatography eluting with hexanes to 8:1 hexanes:ethylacetate to give the title compound (1.65 g, 73%) as a colorless oil. MSES 141 M−1.

Preparation 2 Synthesis of 1-(3-fluoro-2,4-dihydroxy-phenyl)-ethanone

A solution of 2-fluoro-3-methoxy-phenol (0.5 g, 3.53 mmol) anddichloromethane is stirred at −78° C. A 1M solution of boron tribromidein dichloromethane (3.9 mL, 3.9 mmol) is added slowly and the mixture isstirred 10 min cold, then warmed to 0° C. and stirred 1 hr. The reactionis quenched with ice and stirred at room temperature overnight. Theproduct is extracted with ethyl acetate (2×50 mL), dried over magnesiumsulfate, filtered, and concentrated. The resulting residue is combinedwith boron trifluoride diethyl etherate (1.3 mL, 10.3 mmol) and aceticacid (0.2 mL, 3.28 mmol) and heated to reflux 8 hr. The mixture iscooled to room temperature, diluted with water (50 mL), and extractedwith ethyl acetate (3×50 mL). The combined extracts are dried overmagnesium sulfate, filtered and concentrated to about 10 mL volume. Theresulting mixture is diluted with hexanes (50 mL), cooled to 0° C., andfiltered to give the title compound (310 mg, 58%) as a tan solid. MS ES171 M+1.

Preparation 3 Synthesis of 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone

A solution of 2,4,-dihydroxyacetophenone (6 g, 39.4 mmol), aqueous 1Msodium hydroxide (41.4 mL, 41.4 mmol) and water (200 mL) is stirred atroom temperature. An aqueous 1.6M solution of sodium hypochlorite (32mL) is added over a 1 hr period. The resulting dark brown solution isstirred 18 hr at room temperature. The reaction mixture is adjusted to apH of 2-3 with concentrated aqueous hydrochloric acid. The resultingsuspension is filtered and washed with water (4×100 mL). The filteredsolid was dried under vacuum at 45° C. for 2.5 days to give the titlecompound (4.8 g, 65%) as a brown solid. LCMS 1 187 M+.

Preparation 4 Synthesis of1-(3-chloro-2,4-dihydroxy-phenyl)-propan-1-one

The title compound was prepared in a similar manner to1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (Preparation 3) employing2,4-dihydroxypropiophenone to give 4.5 g, 37% of an off-white solid.LCMS 1 201 M+.

Preparation 5 Synthesis of (4-bromo-benzyloxy)-triisopropyl-silane

Stir a solution of 4-bromobenzyl alcohol (50 g, 267.3 mmol), DBU (48 ml,320.8 mmol) and dichloromethane (600 mL) in an ice/water bath. Addtriisopropylsilylchloride (63 mL, 294 mmol) over 10 min via an additionfunnel and stir the reaction mixture for 20 hours at room temperature.Wash the mixture with water (2×600 mL), dry over anhydrous magnesiumsulfate, filter and concentrate. Purify the residue via silicachromatography eluting with 9:1 hexanes:ethyl acetate to give the titlecompound (91.5 g, 99%) as a colorless oil. ¹H NMR (300 MHz, CDC₁₃) δ7.47-7.50 (m, 2H), 7.28-7.30 (m, 2H), 4.81 (s, 1.11-1.24 (m, 21H).

Preparation 6 Synthesis of (3-bromo-benzyloxy)-triisopropyl-silane

The title compound is prepared essentially as described in Preparation 5employing 3-bromobenzyl alcohol to give a colorless oil, 100%. ¹H NMR(CDC₁₃) d 7.54 (s, 1H), 7.20-7.42 (m, 3H), 4.84 (s, 2H), 0.99-1.27 (m,21H).

Preparation 7 Synthesis of3-[hydroxy-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile

Stir a solution of (4-bromo-benzyloxy)-triisopropyl-silane (72 g, 209.7mmol) and tetrahydrofuran (500 mL) at −78° C. Add a 1.6 M solution ofn-butyllithium in hexanes (143 mL) over 10 min. After addition, allowthe reaction mixture to reach −20° C. and stir for 5 minutes. Cool thereaction mixture to −78° C. In another flask, stir a solution of3-cyanobenzaldehyde (25 g, 190.6 mmol) and tetrahydrofuran (250 mL) at−78° C. Add the lithium anion solution to the aldehyde solution vialarge canula at a rate such that the internal aldehyde temperature doesnot rise above −50° C. After addition is complete, stir the reactionmixture 18 hours at room temperature. Dilute the reaction mixture withaqueous saturated ammonium chloride (500 mL) and ethyl acetate (200 mL).Separate the layers, and extract the aqueous layer with ethyl acetate(3×100 mL). Combine the organic layers, dry over anhydrous magnesiumsulfate, filter, and concentrate. Purify the residue via silica gelchromatography eluting with hexanes to 9:1 hexanes:ethyl acetate toafford the title compound (56.1 g, 75%) as a colorless oil. LCMS (m/z)396 M+1.

Preparation 8 Synthesis of3-[(tetrahydro-pyran-2-yloxy)-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile

Stir a solution of3-[hydroxy-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile(12 g, 30.3 mmol), 3,4-dihydro-2H-pyran (3.6 mL, 39.4 mmol) anddichloromethane (250 mL) at room temperature. Add pyridiniump-toluenesulfonate (0.8 g, 3.03 mmol) and stir the resulting mixture 18hours at room temperature. Dilute the reaction mixture with aqueoussaturated sodium hydrogen carbonate (100 mL) and separate the layers.Extract the aqueous layer is washed with dichloromethane (2×50 mL),combine the organic layers, dry with magnesium sulfate, filter andconcentrate. Purify the residue via silica chromatography eluting withhexanes to 8:2 hexanes:ethyl acetate to afford the title compound (14.6g, 100%) as a colorless oil. LCMS (m/z) 478 M−1.

The following compounds are prepared essentially as described inPreparation 8.

Prep. No. Chemical name Structure Physical data 9 3-[(Tetrahydro-pyran-2-yloxy)-(3- triisopropylsilanyloxymethyl- phenyl)-methyl]-benzonitrile

¹H NMR (CDCl₃) δ 7.76 (s, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 7.26- 7.48(m, 5H), 5.89 (s, 1H), 4.86 (s, 2H), 2.29 (bs, 1H), 1.03-1.21 (m, 21H).10 4-[(Tetrahydro- pyran-2-yloxy)-(4- triisopropylsilanyloxymethyl-phenyl)-methyl]- benzonitrile

¹H NMR (DMSO-d₆) δ 7.79- 7.84 (m, 2H), 7.58-7.63 (m, 2H), 7.29-7.40 (m,4H), 5.88 (d, 1H), 4.78 (d, 2H), 4.59-4.60 (m, 1H), 3.64-3.74 (m, 1H),3.39-3.49 (m, 1H), 1.40-1.89 (m, 6H), 0.96- 1.23 (m, 21H).

Preparation 11 Synthesis of3-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

Add a 1M solution in tetrahydrofuran of tetrabutylammonium fluoride (37mL, 37 mmol) to a solution of3-[(tetrahydro-pyran-2-yloxy)-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile(14.6 g, 30.4 mmol) in tetrahydrofuran (50 mL) and tetrahydrofuran stirat room temperature for 2 hours. Concentrate the reaction, dilute withwater (200 mL), and extract with ethyl acetate (2×100 mL). Combine theextracts, dry over magnesium sulfate, filter, and concentrate. Purifythe residue via silica chromatography eluting with 9:1 hexanes:ethylacetate to 1:1 hexanes ethyl acetate to afford the title compound (8.0g, 82%), as a colorless thick oil. LCMS (m/z) 323 M+1.

The following compounds are prepared essentially as described inPreparation 11.

Prep. Chemical Physical No. name Structure data 123-[(3-Hydroxymethyl-phenyl)- (tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

LCMS 322 M − 1 13 4-[(4-Hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)- methyl]-benzonitrile

LCMS 322 M − 1

Preparation 14 Synthesis of3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

Stir a solution of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (1.75 g, 9mmol),3-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(2.9 g, 9 mmol), toluene (10 mL), and dichloromethane (10 mL) at −20° C.Add 1,1′-(azodicarbonyl)dipiperidine (4.5 g, 18 mmol) followed bytributylphosphine (4.5 mL, 18 mmol) and allow the resulting yellowsolution to stir at room temperature overnight. Concentrate theresulting thick reaction mixture and dilute with ether (50 mL). Cool theslurry to 0° C. with stirring, for 30 minutes. Filter the reactionmixture, concentrate, and purify via silica chromatography eluting with1:1 hexanes:(5:4:1 hexanes:dichloromethane:ethyl acetate) to give thetitle compound (3 g, 67%), as an orange thick oil. LCMS (m/z) 498 M−1.

The following compounds are prepared essentially as described inPreparation 14.

Prep. Chemical Physical No. name Structure data 153-[[4-(4-Acetyl-3-hydroxy-2- propyl-phenylsulfanylmethyl)-phenyl]-(tetrahydro-pyran-2- yloxy)-methyl]-benzonitrile

LCMS (m/z) 514 M − 1. 16 3-[[4-(3-Hydroxy-2-methyl-4-propionyl-phenoxymethyl)- phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

LCMS (m/z) m-THP 400. 17 3-[[4-(4-Acetyl-3-hydroxy-2-isopropyl-phenoxymethyl)- phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

LCMS 498 M − 1. 18 3-[[4-(4-Acetyl-2-fluoro-3- hydroxy-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2- yloxy)-methyl]-benzonitrile

LCMS 474 M − 1. 19 3-[[4-(4-Acetyl-2-fluoro-3- hydroxy-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2- yloxy)-methyl]-benzonitrile

LCMS 490 M − 1. 20 3-[[4-(2-Chloro-3-hydroxy-4-propionyl-phenoxymethyl)- phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

LCMS 504 M − 1. 21 3-[[3-(4-Acetyl-3-hydroxy-2- propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2- yloxy)-methyl]-benzonitrile

LCMS 498 M − 1. 22 3-[[3-(4-Acetyl-3-hydroxy-2- methyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2- yloxy)-methyl]-benzonitrile

LCMS 470 M − 1. 23 3-[[3-(3-Hydroxy-2-methyl-4-propionyl-phenoxymethyl)- phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

LCMS 484 M − 1. 24 3-[[3-(4-Acetyl-3-hydroxy-2- propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2- yloxy)-methyl]-benzonitrile

LCMS 498 M − 1. 25 3-[[3-(4-Acetyl-2-chloro-3- hydroxy-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2- yloxy)-methyl]-benzonitrile

¹H NMR (CDCl₃) δ 13.20 (s, 1 H), 7.30- 7.70 (m, 9 H), 6.55 (d, 1 H),5.87 (s, 1 H), 5.28 (s, 2 H), 4.65- 4.69 (m, 1 H), 3.80- 3.85 (m, 1 H),3.50- 3.60 (m, 1 H), 2.63 (s, 3 H), 1.50-1.80 (m, 6 H). 264-[[4-(4-Acetyl-3-hydroxy-2- propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2- yloxy)-methyl]-benzonitrile

LCMS 498 M − 1. 27 3-[[4-(4-Acetyl-3-hydroxy-2- trifluoromethyl-phenoxymethyl)-phenyl]- (tetrahydro-pyran-2-yloxy)- methyl]-benzonitrile

¹H NMR (DMSO-d₆) δ 1.43-1.85 (m, 6 H), 2.63 (s, 3 H), 3.42 (m, 1 H),3.68 (m, 1 H), 4.59 (m, 1 H), 5.34 (d, 2 H), 5.87 (d, 1 H), 6.89 (dd, 1H), 7.39- 7.59 (m, 5 H), 7.73 (m, 2 H), 7.86 (d, 1 H), 8.19 (m, 1 H),13.77 (s, 1 H). 28 3-[[4-(4-Acetyl-2-ethyl-3- hydroxy-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2- yloxy)-methyl]-benzonitrile

MS (esi negative) m/z (rel intensity) 484 (100). 293-[[4-(4-Acetyl-3-hydroxy-2- thiophen-3-yl- phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)- methyl]-benzonitrile

LCMS 538 M − 1. 30 3-[[4-(4-Acetyl-3-hydroxy-2- thiophen-2-yl-phenoxymethyl)-phenyl]- (tetrahydro-pyran-2-yloxy)- methyl]-benzonitrile

LCMS 538 M − 1. 31 3-[[4-(5-Acetyl-4′-fluoro-6- hydroxy-biphenyl-2-yloxymethyl)-phenyl]- (tetrahydro-pyran-2-yloxy)- methyl]-benzonitrile

LCMS 550 M − 1. 32 3-[[4-(4-Acetyl-3-hydroxy-2-pyridin-2-yl-phenoxymethyl)- phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

LCMS 533 M − 1.

Preparation 33 Synthesis of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile

Stir a mixture of3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(13.4 g, 26.88 mmol), p-toluenesulfonic acid monohydrate (5.1 g, 26.88mmol), methanol (100 mL), dichloromethane (50 mL), and ethyl acetate (50mL) at room temperature for an hour. Concentrate the reaction mixture,dilute with ethyl acetate (150 mL) and wash with water (2×100 mL). Drythe organic phase over magnesium sulfate, filter, and concentrate.Dilute the residue with 5:1 hexanes:dichloromethane (50 mL), cool to 0°C. and filter. Collect a second and third crop to give the titlecompound (10.3 g, 93%), as a white solid. LCMS 416 M+1.

The following compounds are prepared essentially as described inPreparation 33.

Prep. Chemical Physical No. name Structure data 343-{[4-(2-Chloro-3-hydroxy-4- propionyl-phenoxymethyl)-phenyl]-hydroxy-methyl}- benzonitrile

LCMS 420 M − 1. 35 3-{[4-(4-Acetyl-2-chloro-3- hydroxy-phenoxymethyl)-phenyl]-hydroxy-methyl}- benzonitrile

LCMS 406 M − 1. 36 3-{[3-(4-Acetyl-3-hydroxy-2- methyl-phenoxymethyl)-phenyl]-hydroxy-methyl}- benzonitrile

LCMS 388 M + 1. 37 3-{Hydroxy-[3-(3-hydroxy-2- methyl-4-propionyl-phenoxymethyl)-phenyl]- methyl}-benzonitrile

LCMS 400 M − 1. 38 3-{[3-(4-Acetyl-3-hydroxy-2- propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}- benzonitrile

LCMS 414 M − 1. 39 3-{[3-(4-Acetyl-2-chloro-3- hydroxy-phenoxymethyl)-phenyl]-hydroxy-methyl}- benzonitrile

LCMS 406 M − 1. 40 4-{[4-(4-Acetyl-3-hydroxy-2- propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}- benzonitrile

LCMS 416 M + 1. 41 3-{[4-(4-Acetyl-3-hydroxy-2- trifluoromethyl-phenoxymethyl)-phenyl]- hydroxy-methyl}-benzonitrile

LCMS (m/e): 440 (M − 1)

Example 1 Synthesis of1-[2-hydroxy-4-(4-{hydroxy-[3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-3-propyl-phenyl]-ethanone

Bring to a heavy reflux, a mixture of3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(3.0 g, 6 mmol), zinc (II) bromide (4.1 g, 18 mmol), sodium azide (2.34g, 36 mmol), water (20 mL) and isopropyl alcohol (20 mL) for 18 hours.Cool and dilute the reaction mixture with water (100 mL) and adjust thepH to 2 with 1M hydrochloric acid. Extract the product with ethylacetate (2×150 mL), combine the extracts and wash with water (100 mL),brine (100 mL), dry over magnesium sulfate, filter, and concentrate.Stir the residue in methanol (50 mL), and add p-toluenesulfonic acidmono hydrate (4 g, 21 mmol) and stir at room temperature for an hour.Concentrate the mixture and dilute with water (100 mL). Extract theproduct with ethyl acetate (2×100 mL). Wash the combined extracts withwater (2×100 mL), brine (100 mL), dry over magnesium sulfate, filter,and concentrate. Purify the resulting residue via silica chromatographyeluting with 1:1 hexanes:ethyl acetate to 1:1 ethyl acetate:acetone toacetone to give the title compound (2.6 g, 95%) as a tan solid. ¹H NMR(DMSO-d₆) δ 12.86 (s, 1H), 8.12 (s, 1H), 7.87 (d, 1H), 7.80 (d, 1H),7.39-7.55 (m, 6H), 6.72 (d, 1H), 6.11 (d, 1H), 5.82 (d, 1H), 5.23 (s,2H), 2.56 (s, 3H), 2.57-2.60 (m, 2H), 1.44-1.52 (m, 2H), 0.87 (t, 3H).LCMS (m/z) 457 M−1.

The following compounds are prepared essentially as described in Example1.

Ex. Chemical Physical No. name Structure data  21-[2-Hydroxy-4-(4-{hydroxy- [3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzylsulfanyl)-3- propyl-phenyl]-ethanone

¹H NMR (DMSO-d₆) d 12.83 (s, 1 H), 8.13 (s, 1 H), 7.88 (d, 1 H), 7.73(d, 1 H), 7.56 (m, 2 H), 7.40 (s, 4 H), 6.97 (d, 1 H), 6.11 (d, 1 H),5.81 (d, 1 H), 4.34 (s, 2 H), 2.60 (m, 5 H), 1.45 (m, 2 H), 0.88 (m, 3H). LCMS (m/z) 473 M − 1.  3 1-[2-Hydroxy-4-(4-{hydroxy-[3-(1H-tetrazol-5-yl)-phenyl]- methyl}- phenylmethanesulfonyl)-3-propyl-phenyl]-ethanone

¹H NMR (DMSO-d₆) d 12.80 (s, 1 H), 8.09 (s, 1 H), 7.96 (d, 1 H), 7.88-7.89 (m, 1 H), 7.50-7.55 (m, 2 H), 7.37 (d, 2 H), 7.27 (d, 1 H), 7.10(d, 2 H), 6.14 (d, 1 H), 5.80 (d, 1 H), 4.64 (s, 2 H), 2.68-2.75 (m, 5H), 1.40-1.50 (m, 2 H), 0.83-91 (m, 3 H). LCMS (m/z) 505 M − 1.  41-[2-Hydroxy-4-(4-{hydroxy- [3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-3- methyl-phenyl]-propan-1-one

¹H NMR (DMSO-d₆) d 12.90 (s, 1 H), 8.15 (s, 1 H), 7.81-7.90 (m, 2 H),7.52-7.62 (m, 2 H), 7.41-7.49 (m, 4 H), 6.72 (d, 1 H), 6.14 (s, 1 H),5.84 (s, 1 H), 5.21 (s, 2 H), 3.04 (q, 2 H), 0.88 (t, 3 H). LCMS 443 M− 1.  5 1-[2-Hydroxy-4-(4-{hydroxy- [3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-3- isopropyl-phenyl]-ethanone

¹H NMR (DMSO-d₆) d 13.06 (s, 1 H), 8.15 (s, 1 H), 7.89 (d, 1 H), 7.78(d, 1 H), 7.52-7.62 (m, 2 H), 7.41-7.49 (m, 4 H), 6.71 (d, 1 H),6.14-6.15 (m, 1 H), 5.84-5.85 (m, 1 H), 5.21 (s, 2 H), 3.52- 3.59 (m, 1H), 2.57 (s, 3 H), 1.24 (d, 6 H). LCMS 457 M − 1.  61-[3-Fluoro-2-hydroxy-4-(4- {hydroxy-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}- benzyloxy)-phenyl]-ethanone

¹H NMR (DMSO-d₆) d 12.34 (s, 1 H), 8.14 (s, 1 H), 7.85 (m, 1 H),7.69-7.75 (2 H), 7.39- 7.58 (m, 5 H), 6.85-6.91 (m, 1 H), 6.15-6.19 (m,1 H), 5.77-5.85 (m, 1 H), 5.28 (s, 2 H), 2.60 (s, 3 H). LCMS 433 M − 1. 7 1-[3-Chloro-2-hydroxy-4-(4- {hydroxy-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}- benzyloxy)-phenyl]-ethanone

¹H NMR (DMSO-d₆) d 12.14 (s, 1 H), 7.75- 7.95 (m, 2 H), 7.69-7.75 (m, 2H), 7.42-7.56 (m, 5 H), 6.90 (d, 1 H), 6.17- 6.19 (m, 1 H), 5.80-5.82(m, 1 H), 5.33 (s, 2 H), 2.62 (s, 3 H). LCMS 449 M − 1.  81-[2-Hydroxy-4-(3-{hydroxy- [3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-3-propyl- phenyl]-ethanone

¹H NMR (DMSO-d₆) d 12.84 (s, 1 H), 8.15 (s, 1 H), 7.87-7.91 (m, 1 H),7.79 (d, 1 H), 7.51-7.59 (m, 3 H), 7.30-7.45 (m, 3 H), 6.72 (d, 1 H),5.85 (s, 1 H), 5.24 (s, 2 H), 2.56-2.59 (m, 5 H), 1.39-1.47 (m, 2 H),0.81 (t, 3 H). LCMS 457 M − 1.  9 1-[2-Hydroxy-4-(4-{hydroxy-[4-(2H-tetrazol-5-yl)-phenyl]- methyl}-benzyloxy)-3-propyl-phenyl]-ethanone

¹H NMR (DMSO-d₆) δ 12.85 (s, 1 H), 7.99 (d, 2 H), 7.79 (d, 1 H), 7.63(d, 2 H), 7.39-7.47 (m, 4 H), 6.72 (d, 1 H), 6.10 (m, 1 H), 5.82 (s, 1H), 5.23 (s, 2 H), 2.56-2.65 (m, 5 H), 1.45-1.53 (m, 2 H), 0.87 (t, 3H). LCMS 459 M + 1. 10 1-[2-Hydroxy-4-(4-{hydroxy-[3-(2H-tetrazol-5-yl)-phenyl]- methyl}-benzyloxy)-3-trifluoromethyl-phenyl]- ethanone

¹H NMR (DMSO-d₆) δ 2.62 (s, 3 H), 5.33 (s, 2 H), 5.83 (d, 1 H), 6.13 (d,1 H), 6.91 (d, 1 H), 7.35-7.59 (m, 6 H), 7.87 (d, 1 H), 8.13 (s, 1 H),8.18 (d, 1 H), 13.77 (s, 1 H); MS (esi negative) m/z 483 (M − 1). 111-[3-Ethyl-2-hydroxy-4-(4- {hydroxy-[3-(2H-tetrazol-5-yl)-phenyl]-methyl}- benzyloxy)-phenyl]-ethanone

¹H NMR (DMSO-d₆) δ 1.02 (t, 3 H), 2.56 (s, 3 H), 2.58 (q, 2 H), 5.22 (s,2 H), 5.82 (d, 1 H), 6.12 (d, 1 H), 6.71 (d, 1 H), 7.39-7.47 (m, 4 H),7.51-7.60 (m, 2 H), 7.87 (dt, 1 H), 8.13 (s, 1 H), 12.82 (s, 1 H); MS(esi negative) m/z 443 (M − 1). 12 3-[4-(4-Acetyl-2-chloro-3- hydroxy-phenylsulfanylmethyl)- benzyl]-benzoic acid

¹H NMR (acetone-d₆) δ 13.10 (s, 1 H), 7.80- 7.89 (m, 3 H), 7.49 (d, 1H), 7.41-7.43 (m, 3 H), 7.25 (d, 2 H), 6.99 (d, 1 H), 4.34 (s, 2 H),4.05 (s, 2 H), 2.63 (s, 3 H). LCMS 425 M − 1.

Preparation 42 Synthesis of dimethyl-thiocarbamic acidS-(4-acetyl-3-hydroxy-2-propyl-phenyl)ester

Stir a mixture of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (2 g, 10.3mmol), triethylamine (1.6 mL 11.3 mmol), and dichloromethane (40 mL) atroom temperature. Add dimethylthiocarbamoyl chloride (1.27 g, 10.3 mmol)and stir at room temperature overnight. Wash the mixture with 1Mhydrochloric acid (25 mL), dry over magnesium sulfate, filter andconcentrate. Purify the residue via silica chromatography eluting withhexanes to 7:3 hexanes:ethyl acetate to afford dimethyl-thiocarbamicacid O-(4-acetyl-3-hydroxy-2-propyl-phenyl) ester (1.2 g, 41%) as alight yellow solid. Stir the yellow solid in tetradecane (10 mL) at 250°C. for an hour and purify by silica chromatography eluting with hexanesto 6:4 hexanes:ethyl acetate to give the title compound (1.08 g, 90%) asa white solid. LCMS (m/z) 280 M−1.

Preparation 43 Synthesis of1-(2-hydroxy-4-mercapto-3-propyl-phenyl)-ethanone

Reflux a stirred mixture of dimethyl-thiocarbamic acidS-(4-acetyl-3-hydroxy-2-propyl-phenyl) ester (1.08 g, 3.84 mmol),potassium hydroxide (1.1 g, 19.2 mmol), ethanol (25 mL), and water (10mL) for 2 hours. Cool the reaction in an ice/water bath and adjust thepH to 2 with aqueous 5N hydrochloric acid. Extract the mixture withethyl acetate (3×50 mL). Combine the extracts and wash with water (50mL) and brine (50 mL) and dry over magnesium sulfate, filter, andconcentrate to afford the title compound (0.76 g, 94%) as a brown oilwhich solidifies on standing. LCMS (m/z) 211 M−1.

Preparation 44 Synthesis of3-[[4-(4-acetyl-3-hydroxy-2-propyl-benzenesulfonylmethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

Stir a mixture of3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(140 mg, 0.271 mmol) and dichloromethane (5 mL) at room temperature. Add3-chloroperoxybenzoic acid (50-55% pure) (100 mg, 0.29 mmol) and stirthe reaction for 10 minutes. Add an additional portion of3-chloroperoxybenzoic acid (50-55% pure) (280 mg, 0.81 mmol) and stirthe reaction for an additional hour at room temperature. Dilute thereaction with aqueous saturated sodium hydrogen carbonate (50 mL) andwater (50 mL). Extract the product with dichloromethane (2×50 mL). Washthe combined extracts with water (50 mL), brine (50 mL), and dry oversodium sulfate, filter, and concentrate. Purify the product via silicachromatography eluting with hexanes to 3:1 ethyl acetate:hexanes to givethe title compound (147 mg, 99%) as a white solid. LCMS (m/z) 546 M−1.

Preparation 45 Synthesis of3-[3-(4-acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-benzyl]-benzoicacid methyl ester

Stir a mixture of 1-(2-Hydroxy-4-mercapto-3-propyl-phenyl)-ethanone (132mg, 0.63 mmol), 3-(3-Iodomethyl-benzyl)-benzoic acid methyl ester (230mg, 0.63 mmol), and cesium carbonate (410 mg, 1.26 mmol) in 2-butanone(6 ml) at room temperature under argon for 20 hours. Pour the mixtureinto water (60 ml) and extract with ethyl acetate (2×30 ml). Combine theorganic extracts and wash with water, brine, then dry over sodiumsulfate, filter and concentrate. Purify the crude product via silicachromatography eluting with 1:4 ethyl acetate:hexanes to give the titlecompound (240 mg, 85%). MS (m/z) 447 (M−H).

Example 13 Synthesis of3-[3-(4-aetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-benzyl]-benzoicacid

Dissolve3-[3-(4-Acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-benzyl]-benzoicacid methyl ester (238 mg, 0.53 mmol) in tetrahydrofuran (5 ml) andmethanol (4 ml). Add lithium hydroxide monohydrate (89 mg, 2.1 mmol) andwater (1.5 ml), then stir at room temperature for 18 hours. Cool at 0°C. and adjust to pH 3 with 1 N hydrochloric acid. Dilute with water (35ml) and extract with ethyl acetate (2×20 ml). Combine the organicextracts, dry over sodium sulfate, filter and concentrate to a solid.Purify the crude product via reverse phase HPLC using a gradient of90:10 to 20:80 (water/0.1% TFA):acetonitrile as eluent to give the titlecompound (196 mg, 85%). MS (m/z) 433 (M−H), ¹H NMR (400 MHz, DMSO-d₆)12.85 (s, 1H), 7.80-7.75 (m, 2H), 7.68 (d, 1H), 7.47-7.38 (m, 2H),7.31-7.26 (m, 3H), 7.17-7.14 (m, 1H), 6.94 (d, 1H), 4.32 (s, 2H), 4.02(s, 2H), 2.63-2.59 (m, 5H), 1.43 (sextet, 2H), 0.90 (t, 3H).

The following compounds are prepared essentially as described in Example13.

Ex. Chemical Physical No. name Structure data 14 4-[3-(4-Acetyl-3-hydroxy-2-propyl- phenylsulfanylmethyl)- benzyl]-benzoic acid

¹H NMR (400 MHz, DMSO-d₆) 12.85 (s, 1 H), 7.85-7.83 (m, 2 H), 7.68 (d, 1H), 7.32-7.24 (m, 5 H), 7.17-7.13 (m, 1 H), 6.90 (d, 1 H), 4.32 (s, 2H), 4.00 (s, 2 H), 2.63- 2.59 (m, 5 H), 1.44 (sextet, 2 H), 0.90 (t, 3H). MS (m/z) 433 (M − H). 15 3-[4-(4-Acetyl-3- hydroxy-2-propyl-phenylsulfanylmethyl)- benzyl]-benzoic acid

¹H NMR (400 MHz, DMSO-d₆) 12.8 (s, 1 H), 7.80-7.7.76 (m, 2 H), 7.73 (d,1 H), 7.50-7.35 (m, 4 H), 7.23-7.20 (m, 2 H), 6.96 (d, 1 H), 4.32 (s, 2H), 4.00 (s, 2 H), 2.63- 2.60 (m, 5 H), 1.45 (sextet, 2 H), 0.90 (t, 3H). MS (m/z) 433 (M − H). 16 4-[4-(4-Acetyl-3- hydroxy-2-propyl-phenylsulfanylmethyl)- benzyl]-benzoic acid

¹H NMR (400 MHz, DMSO-d₆) 12.75 (2 H), 7.86 (d, 2 H), 7.72 (d, 1 H),7.37-7.33 (m, 4 H), 7.21 (d, 2 H), 6.97 (d, 1 H), 4.30 (s, 2 H), 4.00(s, 2 H), 2.62-2.60 (m, 5 H), 1.45 (sextet, 2 H), 0.90 (t, 3 H). MS(m/z) 433 (M − H). 17 3-[3-(4-Acetyl-3- hydroxy-2-methyl-phenylsulfanylmethyl)- benzyl]-benzoic acid

¹H NMR (400 MHz, DMSO-d₆) 12.9 (s, 1 H), 12.8 (s, 1 H), 7.80- 7.76 (m, 2H), 7.69 (d, 1 H), 7.49- 7.39 (m, 2 H), 7.33-7.32 (m, 1 H), 7.28-7.27(m, 2 H), 7.17-7.14 (m, 1 H), 6.93 (d, 1 H), 4.33 (s, 2 H), 4.01 (s, 2H), 2.60 (s, 3 H), 2.09 (s, 3 H). MS (m/z) 405 (M − H). 184-[3-(4-Acetyl-3- hydroxy-2-methyl- phenylsulfanylmethyl)-benzyl]-benzoic acid

¹H NMR (DMSO-d6) δ 12.81 (s, 2 H), 7.83 (d, J = 8.3 Hz, 2 H), 7.67 (d, J= 8.8 Hz, 1 H), 7.31- 7.22 (m, 5 H), 7.13 (d, J = 6.0 Hz, 1 H), 6.90 (d,J = 8.8 Hz, 1 H), 4.30 (s, 2 H), 3.98 (s, 2 H), 2.58 (s, 3 H), 2.06 (s,3 H); MS (m/e): 407 (M + 1). 19 3-[4-(4-Acetyl-3- hydroxy-2-methyl-phenylsulfanylmethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d6) δ 12.85 (s, 1 H), 12.81 (s, 1 H), 7.77-7.69 (m, 3 H),7.47 (m, 1 H), 7.41-7.34 (m, 3 H), 7.19 (d, J = 8.2 Hz, 2 H), 6.92 (d, J= 8.7 Hz, 1 H), 4.30 (s, 2 H), 3.97 (s, 2 H), 2.57 (s, 3 H), 2.07 (s, 3H); MS (m/e): 407 (M + 1). 20 4-[4-(4-Acetyl-3- hydroxy-2-methyl-phenylsulfanylmethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 12.81 (s, 1 H), 12.78 (s, 1 H), 7.80 (d, J = 8.0 Hz,2 H), 7.71 (d, J = 8.7 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.24 (d, J =8.2 Hz, 2 H), 7.18 (d, J = 8.0 Hz, 2 H), 6.92 (d, J = 8.7 Hz, 1 H), 4.30(s, 2 H), 3.94 (s, 2 H), 2.57 (s, 3 H), 2.07 (s, 3 H); MS (m/e): 407(M + 1). 21 1-(2-Hydroxy-3- methyl-4-{4-[3- (1H-tetrazol-5-yl)- benzyl]-benzylsulfanyl}- phenyl)-ethanone

¹H NMR (400 MHz, DMSO-d₆) 12.85 (s, 1 H), 7.94-7.93 (m, 1 H), 7.87-7.85(m, 1 H), 7.73 (d, 1 H), 7.55-7.45 (m, 2 H), 7.39 (d, 2 H), 7.26 (d, 2H), 6.95 (d, 1 H), 4.33 (s, 2 H), 4.03 (s, 2 H), 2.60 (s, 3 H), 2.09 (s,3 H). MS (m/z) 429 (M − H). 22 1-(2-Hydroxy-3- propyl-4-{4-[3-(1H-tetrazol-5-yl)- benzyl]- benzylsulfanyl}- phenyl)-ethanone

¹H NMR (400 MHz, DMSO-d₆) 12.80 (s, 1 H), 7.94-7.93 (m, 1 H), 7.87-7.84(m, 1 H), 7.72 (d, 1 H), 7.55-7.51 (m, 1 H), 7.48-7.45 (m, 1 H),7.39-7.37 (m, 1 H), 7.27- 7.25 (m, 1 H), 6.96 (d, 1 H), 4.32 (s, 2 H),4.03 (s, 2 H), 2.63-2.60 (m, 5 H), 1.45 (sextet, 2 H), 0.89 (t, 3 H). MS(m/z) 457 (M − H).

Preparation 46 Synthesis of(S)-3-[(4-Iodomethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

Add sequentially a solution of(S)-3-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(2.0 g, 6.18 mmol) dichloromethane (20 ml) and a solution of iodine(1.72 g, 6.80 mmol) in dichloromethane (30 ml) to a cooled (0° C.)solution of triphenylphosphine (1.78 g, 6.80 mmol) and imidazole (635mg, 9.33 mmol) in dichloromethane (20 ml). Allow to warm to roomtemperature, then stir for 1.5 hours. Pour the mixture into a cold (0°C.) solution of sodium thiosulfate (3.63 g, 23 mmol) in an ice/watermixture (250 g) and stir for 30 minutes. Extract the aqueous layer withdichloromethane (30 ml). Combine the organic extracts and wash withwater, dry with sodium sulfate, filter and concentrate. Purify the crudeproduct via silica chromatography eluting with 15:85 ethylacetate:hexanes to give the title compound (2.19 g, 82%). MS (m/z).Parent ion not observed.

Preparation 47 Synthesis of(S)-3-[[4-(4-Acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

Stir a mixture of 1-(2-Hydroxy-4-mercapto-3-propyl-phenyl)-ethanone (250mg, 1.18 mmol),(S)-3-[(4-Iodomethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(515 mg, 1.18 mmol) and cesium carbonate (769 mg, 2.36 mmol) in2-butanone (10 ml) at room temperature under argon for 24 hours. Pourthe mixture into water (85 ml) and extract with ethyl acetate (3×25 ml).Combine the organic extracts and wash with water, brine, then dry oversodium sulfate, filter and concentrate. Purify the crude product viasilica chromatography eluting with 1:4 ethyl acetate:hexanes to give thetitle compound (325 mg, 53%). MS (m/z) 514 (M−H).

Preparation 48 Synthesis of(S)-3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-phenyl]-hydroxy-methyl}-benzonitrile

Add p-toluenesulfonic acid monohydrate (78 mg, 0.41 mmol) to a solutionof(S)-3-[[4-(4-Acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(177 mg, 0.34 mmol) in methanol (5 ml) at room temperature. Stir themixture for 1.5 hours, concentrate, and dissolve the residue in ethylacetate (25 ml) and saturated aqueous sodium bicarbonate (35 ml). Washthe organic layer with saturated aqueous sodium bicarbonate, brine, dryover sodium sulfate and concentrate. Purify the crude product via silicachromatography eluting with 1:2 ethyl acetate:hexanes to give the titlecompound (122 mg, 84%). MS (m/z) 430 (M−H).

Example 23 Synthesis of(S)-1-[2-hydroxy-4-(4-{hydroxy-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzylsulfanyl)-3-propyl-phenyl]-ethanone

Add sodium azide (66 mg, 0.25 mmol) and zinc bromide (131 mg, 0.50 mmol)to a solution of(S)-3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-phenyl]-hydroxy-methyl}-benzonitrile(110 mg, 0.25 mmol) in N-methylpyrrolidinone (2.0 ml). Heat the mixtureat 140° C. for 12 hours, then cool to room temperature and stir for 18hours. Pour the mixture into water (25 ml) and stir the solid suspensionfor 20 minutes. Filter and wash the filtered solid with water. Dissolvethe solid in a 1N HCl (25 ml) and ethyl acetate (20 ml) mixture. Extractthe aqueous layer with ethyl acetate (25 ml), combine the organicextracts, then wash with water, brine, dry over sodium sulfate andconcentrate. Purify the crude product via reverse phase HPLC using agradient of 90:10 to 20:80 (water/0.1% TFA):acetonitrile as eluent togive the title compound (37 mg, 31%). MS (m/z) 473 (M−H), ¹H NMR (400MHz, DMSO-d₆) 12.83 (s, 1H), 8.13-8.11 (m, 1H), 7.89-7.86 (m, 1H), 7.72(d, 1H), 7.59-7.51 (m, 2H), 7.41-7.37 (m, 4H), 6.96 (d, 1H), 5.60 (s,1H), 4.30 (s, 2H), 2.65-2.60 (m, 5H), 1.45 (sextet, 2H), 0.90 (t, 3H).

Preparation 49 Synthesis of1-(2-Hydroxy-3-methyl-4-nitro-phenyl)-ethanone

To a solution of 2-methyl-3-nitrophenol (2.0 g, 13 mmol) in nitrobenzene(16 mL) at RT under Ar gas is added AlCl₃ (3.9 g, 29 mmol). The reddishmixture is heated to 50° C. To the reddish mixture is added dropwise viaaddition funnel a solution of acetyl chloride (1.2 mL, 17 mmol) innitrobenzene (10 mL). The reaction is heated to 120° C. After 2 h at120° C., the reaction mixture is cooled to RT and quenched slowly into a1N HCl/ice mixture. The resulting mixture is stirred for 30 min andextracted with EtOAc (3×). The organic layers are combined andconcentrated. Water is used to azeotrope off the nitrobenzene. Theresulting residue is purified by flash column chromatography using 20%EtOAc/hexane. Obtained is the title compound as reddish oil (1.2 g). Thetitle compound is 60% pure by LC-MS. Compound is used as is in the nextstep. LC-MS (m/e): 194 (M−1).

Preparation 50 Synthesis of1-(4-Amino-2-hydroxy-3-methyl-phenyl)-ethanone

To a solution of 1-(2-hydroxy-3-methyl-4-nitro-phenyl)-ethanone (720 mg,3.7 mmol) in EtOH (30 mL) are consecutively added Fe powder (4 g, 74mmol), water (7.2 mL), and conc. HCl (145 μL). The reaction mixture isheated at 95° C. for 4 h. The iron is filtered through celite and thefiltrate poured slowly into saturated aqueous NaHCO₃. After the bubblingsubsides, the mixture is extracted with EtOAc (3×). The organic layersare combined, washed with brine, dried over Na₂SO₄, and concentrated.The residue is purified by 25% EtOAc/hexane. Obtained is the titlecompound as a white solid (455 mg). LC-MS (m/e): 166 (M+1).

Preparation 51 Synthesis of1-(4-Amino-2-hydroxy-3-propyl-phenyl)-ethanone

To N1-(4-acetyl-3-hydroxy-2-propylphenyl)acetamide (1.0 g, 4.3 mmol) inabsolute ethanol (15 mL) is added 6N HCl (15 mL). The reaction mixtureis refluxed for 3 h. The reaction mixture is cooled to RT and quenchedinto saturated aqueous NaHCO₃. The mixture is extracted with EtOAc (3×).The organic layers are combined, washed with brine, dried over Na₂SO₄and concentrated. Obtained is the title compound (827 mg, 99%). LC-MS(m/e): 194 (M+1).

Preparation 52 Synthesis of3-[{4-[(4-Acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-phenyl}-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

To a solution of 1-(4-amino-2-hydroxy-3-methyl-phenyl)-ethanone (300 mg,1.8 mmol) and3-[(4-iodomethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(865 mg, 2.0 mmol)) in anhydrous DMF (1.5 mL) under Ar gas at RT isadded K₂CO₃ (303 mg, 2.2 mmol). The reaction mixture is heated at 50° C.overnight. The reaction mixture is quenched into water and extractedwith EtOAc (3×). The organic layers are combined, washed with brine,dried over Na₂SO₄ and concentrated. The residue is purified by flashchromatography using 25% EtOAc/hexane as eluent. Obtained is the titlecompound as a yellow foam (538 mg, 64%). LC-MS (m/e): 469 (M−1).

The following compounds are prepared essentially by the method ofpreparation 52.

Prep. Chemical Physical No. name Structure data 53 3-{3-[(4-Acetyl-3-hydroxy-2-methyl- phenylamino)- methyl]-benzyl}- benzoic acid methylester

LC-MS (m/e): 404 (M + 1). 54 4-{4-[(4-Acetyl-3- hydroxy-2-methyl-phenylamino)- methyl]-benzyl}- benzoic acid methyl ester

LC-MS (m/e): 404 (M + 1). 55 4-{3-[(4-Acetyl-3- hydroxy-2-methyl-phenylamino)- methyl]-benzyl}- benzoic acid methyl ester

LC-MS (m/e): 404 (M + 1). 56 3-{4-[(4-Acetyl-3- hydroxy-2-methyl-phenylamino)- methyl]-benzyl}- benzoic acid methyl ester

LC-MS (m/e): 404 (M + 1). 57 3-{4-[(4-Acetyl-3- hydroxy-2-methyl-phenylamino)- methyl]-benzyl}- benzonitrile

LC-MS (m/e): 414 (M + 1). 58 3-{4-[(4-Acetyl-3- hydroxy-2-propyl-phenylamino)- methyl]-benzyl}- benzoic acid methyl ester

LC-MS (m/e): 432 (M + 1). 59 3-[{4-[(4-Acetyl-3- hydroxy-2-propyl-phenylamino)- methyl]-phenyl}- (tetrahydro-pyran-2- yloxy)-methyl]-benzonitrile

LC-MS (m/e): 499 (M + 1). 60 4-[{4-[(4-Acetyl-3- hydroxy-2-methyl-phenylamino)- methyl]-phenyl}- (tetrahydro-pyran-2- yloxy)-methyl]-benzonitrile

LC-MS (m/e): 469 (M − 1).

Preparation 61 Synthesis of3-({4-[(4-acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-phenyl}-hydroxy-methyl)-benzonitrile

To3-[{4-[(4-acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-phenyl}-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(538 mg, 1.1 mmol) in MeOH (5 mL) is added conc. HCl (0.33 mL). Thereaction mixture is stirred at RT for 6 h. The reaction mixture isconcentrated and the residue partitioned between saturated aqueousNaHCO₃ and EtOAc. The organic layer is separated and the aqueousextracted with EtOAc (2×). The organic layers are combined, washed withbrine, dried over Na₂SO₄, and concentrated. The residue is purified byflash column chromatography using 40% EtOAc/hexane as eluent. Obtainedis the title compound as yellow foam (305 mg, 72%). LC-MS (m/e): 385(M−1).

Example 24 Synthesis of3-({4-[(4-acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-phenyl}-hydroxy-methyl)-benzoicacid

To3-({4-[(4-Acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-phenyl}-hydroxy-methyl)-benzonitrile(160 mg, 0.41 mmol) in EtOH/H₂O (6:1, 2.1 mL) in a microwave tube isadded powdered KOH (140 mg, 2.0 mmol). The tube is sealed, placed in amicrowave reactor, and heated at 150° C. for 30 min. The reactionmixture is acidified to pH=7 and concentrated. The residue is purifiedby reverse phase HPLC using 90:10 to 20:80 (H₂O/0.1% TFA)/CH₃CN.Obtained is the title compound as a brownish solid (86 mg, 52%). LC-MS(m/e): 404 (M−1); ¹H NMR (DMSO-d₆) δ 13.16 (1H, s), 12.85 (1H, bs), 7.90(1H, m), 7.73 (1H, m), 7.56 (1H, m), 7.32-7.45 (2H, m), 7.27 (2H, d),7.20 (2H, d), 6.76 (1H, t), 6.00 (1H, d), 5.69 (1H, s), 4.38 (2H, d),2.35 (3H, s), 1.93 (3H, s).

Preparation 62 Synthesis of3-[(4-{[(4-acetyl-3-hydroxy-2-methyl-phenyl)-methyl-amino]-methyl}-phenyl)-hydroxy-methyl]-benzonitrile

To3-({4-[(4-acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-phenyl}-hydroxy-methyl)-benzonitrile(138 mg, 0.36 mmol) in acetonitrile (14 mL) are added 37% aqueoussolution of formaldehyde (140 μL) and NaCNBH₃ (69 mg, 1.1 mmol). The pHof the mixture is adjusted to approximately 2 by dropwise addition of 1N HCl over a 15 min period. The reaction was complete after 1.5 h,during which time the pH of the reaction mixture is monitored every 15min using pH paper and kept at around 2 by addition of 1N HCl. Thereaction mixture is quenched into H₂O and basified with saturatedaqueous NaHCO₃. The mixture is extracted with EtOAc (3×), washed withbrine, dried over Na₂SO₄, and concentrated. Obtained is the titlecompound as a yellow oil (135 mg, 94%). LC-MS (m/e): 399 (M−1).

The following compound is prepared essentially by the method ofpreparation 62.

Prep. Chemical Physical No. name Structure data 63 3-(4-{[(4-Acetyl-3-hydroxy-2-methyl- phenyl)-methyl- amino]-methyl}- benzyl)-benzonitrile

LC-MS (m/e): 404 (M − 1).

Example 25 Synthesis of3-[(4-{[(4-acetyl-3-hydroxy-2-methyl-phenyl)-methyl-amino]-methyl}-phenyl)-hydroxy-methyl]-benzoicacid

The title compound is prepared essentially as described for3-({4-[(4-acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-phenyl}-hydroxy-methyl)-benzoicacid employing3-[(4-{[(4-acetyl-3-hydroxy-2-methyl-phenyl)-methyl-amino]-methyl}-phenyl)-hydroxy-methyl]-benzonitrile.LC-MS (m/e): 420 (M+1). ¹H NMR (DMSO-d₆) δ 12.87 (1H, s), 7.91 (1H, m),7.73 (1H, m), 7.63 (1H, d), 7.57 (1H, m), 7.37 (1H, dd), 7.29 (2H, d),7.19 (2H, d), 6.55 (1H, d), 5.71 (1H, s), 4.17 (2H, s), 2.62 (3H, s),2.50 (s, 3H), 2.08 (3H, s).

The following compounds are prepared essentially by the method describedin Example 25.

Ex. Chemical Physical No. name Structure data 26 4-({4-[(4-Acetyl-3-hydroxy-2-methyl- phenylamino)- methyl]-phenyl}- hydroxy-methyl)-benzoic acid

LC-MS (m/e): 404 (M − 1); ¹H NMR (DMSO-d₆) δ 13.16 (1 H, s), 12.75 (1 H,bs), 7.81 (2 H, d), 7.43 (3 H, m), 7.15- 7.30 (4 H, m), 6.77 (1 H, m),5.99 (1 H, d), 5.68 (1 H, s), 4.37 (2 H, d), 2.35 (3 H, s), 1.93 (3 H,s). 27 3-({4-[(4-Acetyl-3- hydroxy-2-propyl- phenylamino)-methyl]-phenyl}- hydroxy-methyl)- benzoic acid

LC-MS (m/e): 432 (M − 1); ¹H NMR (DMSO-d₆) δ 13.15 (1 H, s), 12.85 (1 H,bs), 7.89 (1 H, m), 7.72 (1 H, m), 7.55 (1 H, m), 7.34-7.43 (2 H, m),7.27 (2 H, d), 7.18 (2 H, d), 6.87 (1 H, t), 5.97 (1 H, d), 5.69 (1 H,s), 4.37 (2 H, d), 2.48 (2 H, m), 2.34 (3 H, s), 1.41 (2 H, m), 0.90 (3H, t). 28 3-(4-{[(4-Acetyl-3- hydroxy-2-methyl- phenyl)-methyl-amino]-methyl}- benzyl)-benzoic acid

LC-MS (m/e): 404 (M + 1); ¹H NMR (DMSO-d₆) δ 12.87 (1 H, s), 12.85 (1 H,s), 7.73 (2 H, m), 7.63 (1 H, d), 7.44 (1 H, m), 7.37 (1 H, dd), 7.16 (4H, s), 6.54 (1 H, d), 4.17 (2 H, s), 3.95 (2 H, s), 2.63 (3 H, s), 2.51(3 H, s), 2.08 (3 H, s). 29 1-(2-Hydroxy-3- methyl-4-{4-[3-(2H-tetrazol-5-yl)-benzyl]- benzylamino}- phenyl)-ethanone

LC-MS (m/e): 414 (M + 1); ¹H NMR (DMSO-d₆) δ 13.16 (1 H, s), 7.87 (1 H,s), 7.79 (1 H, m), 7.47 (1 H, dd), 7.41 (2 H, m), 7.19 (4 H, m), 6.76 (1H, t), 6.01 (1 H, d), 4.39 (2 H, d), 3.96 (2 H, s), 2.35 (3 H, s), 1.94(3 H, s)

Example 30 Synthesis of3-{4-[(4-Acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-benzyl}-benzoicacid

To3-{4-[(4-acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-benzyl}-benzoicacid methyl ester (356 mg, 0.88 mmol) in THF (14 mL) is added a solutionof LiOH.H₂O (185 mg, 4.4 mmol) in H₂O (7 mL). The reaction mixture isstirred at RT overnight. The reaction mixture is acidified to pH=7 andconcentrated. The residue is purified by reverse phase HPLC using 90:10to 20:80 (H₂O/0.1% TFA)/CH₃CN. Obtained is the title compound as abrownish solid (158 mg, 46%). LC-MS (m/e): 390 (M+1); ¹H NMR (DMSO-d₆) δ13.16 (1H, s), 12.84 (1H, bs), 7.71 (2H, m), 7.43 (2H, m), 7.36 (1H,dd), 7.19 (2H, d), 7.14 (2H, d), 6.75 (1H, t), 6.05 (1H, d), 4.38 (2H,d), 3.92 (2H, s), 2.35 (3H, s), 1.94 (3H, s).

The following compounds are prepared essentially by the method describedin Example 30.

Ex. Chemical Physical No. name Structure data 31 4-{3-[(4-Acetyl-3-hydroxy-2-methyl- phenylamino)- methyl]-benzyl}- benzoic acid

LC-MS (m/e): 390 (M + 1); ¹H NMR (DMSO-d₆) δ 13.17 (1 H, s), 12.75 (1 H,s), 7.79 (2 H, d), 7.41 (1 H, d), 7.25 (2 H, d), 7.17 (2 H, m), 7.07 2H, m), 6.74 (1 H, t), 5.99 (1 H, d), 4.39 (2 H, d), 3.93 (2 H, s), 2.36(3 H, s), 1.93 (3 H, s). 32 3-{3-[(4-Acetyl-3- hydroxy-2-methyl-phenylamino)- methyl]-benzyl}- benzoic acid

LC-MS (m/e): 390 (M + 1); ¹H NMR (DMSO-d₆) δ 13.16 (1 H, s), 12.85 (1 H,bs), 7.72 (2 H, m), 7.40 (2 H, m), 7.35 (1 H, dd), 7.19 (1 H, dd), 7.15(1 H, s), 7.17 (2 H, m), 6.75 (1 H, t), 6.00 (1 H, d) 4.38 (2 H, d),3.93 (2 H, s), 2.36 (3 H, s), 1.93 (3 H, s). 33 4-{4-[(4-Acetyl-3-hydroxy-2-methyl- phenylamino)- methyl]-benzyl}- benzoic acid

LC-MS (m/e): 390 (M + 1); ¹H NMR (DMSO-d₆) δ 13.17 (1 H, s), 12.75 (1 H,s), 7.80 (2 H, d), 7.42 (1 H, d), 7.28 (2 H, d), 7.19 (2 H, d), 7.14 (2H, d), 6.75 (1 H, t), 6.01 (1 H, d), 4.38 (2 H, d), 3.92 (2 H, s), 2.35(3 H, s), 1.94 (3 H, s). 34 3-{4-[(4-Acetyl-3- hydroxy-2-propyl-phenylamino)- methyl]-benzyl}- benzoic acid

LC-MS (m/e): 418 (M + 1); ¹H NMR (DMSO-d₆) δ 13.15 (1 H, s), 12.84 (1 H,s), 7.72 (2 H, m), 7.32-7.47 (3 H, m), 7.15 (4 H, m), 6.86 (1 H, t),5.98 (1 H, d), 4.38 (2 H, d), 3.91 (2 H, s), 2.48 (2 H, m), 2.33 (3 H,s), 1.41 (2 H, m), 0.90 (3 H, t).

Example 35 Synthesis of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoicacid

A mixture of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile(320 mg, 0.772 mmol), potassium hydroxide (1.0 g, 17.85 mmol), water (2mL), and ethanol (10 mL) is stirred at reflux overnight. The reaction iscooled, the pH is adjusted to 2 with aqueous 5N hydrochloric acid anddiluted with water (50 mL). The product is extracted with ethyl acetate(2×50 mL). The combined extracts are washed with water (50 mL), driedover magnesium sulfate, filtered and concentrated to give the titlecompound (250 mg, 75%) as a white powder. ¹H NMR (DMSO-d₆) δ 12.85 (bs,2H), 7.98 (s, 1H), 7.80 (d, 2H), 7.64 (d, 1H), 7.38-7.47 (m, 5H), 6.72(d, 1H), 6.05 (d, 1H), 5.81 (d, 1H), 5.23 (s, 2H), 2.56-2.61 (m, 5H),1.45-1.53 (m, 2H), 0.87 (t, 3H). LCMS 433 M−1.

The following compounds are prepared essentially by the method describedin Example 35.

Ex. Chemical Physical No. name Structure data 36 3-{[4-(4-Acetyl-2-chloro-3-hydroxy- phenoxymethyl)- phenyl]-hydroxy- methyl}-benzoic acid

¹H NMR (DMSO-d₆) d 13.14 (s, 1 H), 12.9 (bs, 1 H), 9.93- 7.99 (m, 2 H),7.80 (d, 1 H), 7.64 (d, 1 H), 7.43-7.47 (m, 5 H), 6.89 (d, 1 H), 6.07(s, 1 H), 5.82 (s, 1 H), 5.33 (s, 2 H), 2.62 (s, 3 H). LCMS 425 M − 1.37 3-{[4-(2-Chloro-3- hydroxy-4-propionyl- phenoxymethyl)-phenyl]-hydroxy- methyl}-benzoic acid

¹H NMR (DMSO-d₆) d 13.20 (bs, 1 H), 13.18 (s, 1 H), 7.94- 7.98 (m, 3 H),7.80 (d, 1 H), 7.64 (d, 1 H), 7.42-7.47 (m, 4 H), 6.88 (d, 1 H), 6.08(s, 1 H), 5.81 (s, 1 H), 5.31 (s, 2 H), 3.06-3.11 (m, 2 H), 1.08 (t, 3H). LCMS 439 M − 1. 38 3-{Hydroxy-[4-(3- hydroxy-2-methyl-4- propionyl-phenoxymethyl)- phenyl]-methyl}- benzoic acid

¹H NMR (DMSO-d₆) d 12.99 (s, 1 H), 12.91 (s, 1 H), 7.96 (s, 1 H), 7.83(d, 2 H), 7.63 (d, 1 H), 7.40-7.51 (m, 5 H), 6.72 (d, 1 H), 5.47 (s, 1H), 5.22 (s, 2 H), 3.30 (s, 3 H), 3.01-3.09 (m, 2 H), 2.04 (s, 3 H),1.10 (t, 3 H). LCMS 419 M − 1. 39 3-{[4-(4-Acetyl-3-hydroxy-2-isopropyl- phenoxymethyl)- phenyl]-hydroxy- methyl}-benzoicacid

¹H NMR (DMSO-d₆) d 13.06 (s, 1 H), 12.92 (s, 1 H), 7.78- 7.82 (m, 3 H),7.51-7.52 (m, 1 H), 7.39-7.46 (m, 3 H), 7.29-7.32 (m, 2 H), 6.72 (d, 1H), 6.14-6.15 (m, 1 H), 5.84-5.85 (m, 1 H), 5.21 (s, 2 H), 3.52-3.59 (m,1 H), 2.58 (s, 3 H), 1.24 (d, 6 H). LCMS 433 M − 1. 403-{[3-(4-Acetyl-3- hydroxy-2-methyl- phenoxymethyl)- phenyl]-hydroxy-methyl}-benzoic acid

¹H NMR (DMSO-d₆) δ 12.9 (s, 1 H), 12.85 (s, 1 H), 7.99 (s, 1 H),7.78-7.81 (m, 2 H), 7.62-7.64 (m, 1 H), 7.31-7.48 (m, 5 H), 6.73 (d, 1H), 6.08 (d, 1 H), 5.81 (d, 1 H), 5.24 (s, 2 H), 2.59 (s, 3 H), 2.01 (s,3 H). LCMS 405 M − 1. 41 3-{Hydroxy-[3-(3- hydroxy-2-methyl-4-propionyl- phenoxymethyl)- phenyl]-methyl}- benzoic acid

¹H NMR (DMSO-d₆) δ 12.93 (s, 1 H), 12.91 (s, 1 H), 7.99 (s, 1 H),7.72-7.84 (m, 2 H), 7.63 (d, 1 H), 7.30-7.48 (m, 5 H), 6.72 (d, 1 H),6.08 (d, 1 H), 5.82 (d, 1 H), 5.23 (s, 1 H), 3.05 (q, 2 H), 2.02 (s, 3H), 1.11 (t, 3 H). LCMS 419 M − 1. 42 3-{[3-(4-Acetyl-3-hydroxy-2-propyl- phenoxymethyl)- phenyl]-hydroxy- methyl}-benzoic acid

¹H NMR (DMSO-d₆) δ 12.93 (s, 1 H), 12.85 (s, 1 H), 7.99 (s, 1 H), 7.79(d, 2 H), 7.62 (d, 1 H), 7.29-7.48 (m, 5 H), 6.72 (d, 1 H), 6.07 (d, 1H), 5.81 (d, 1 H), 5.23 (s, 2 H), 2.53- 2.58 (m, 5 H), 1.43-1.50 (m, 2H), 0.85 (t, 3 H). LCMS 433 M − 1. 43 3-{[3-(4-Acetyl-2-chloro-3-hydroxy- phenoxymethyl)- phenyl]-hydroxy- methyl}-benzoic acid

¹H NMR (DMSO-d₆) δ 13.15 (s, 1 H), 12.92 (bs, 1 H), 7.98 (s, 1 H), 7.93(d, 1 H), 7.80 (d, 1 H), 7.62 (d, 1 H), 7.35-7.51 (m, 5 H), 6.89 (d, 1H), 6.10 (d, 1 H), 5.81 (d, 1 H), 5.34 (s, 2 H), 2.63 (s, 3 H). LCMS 425M − 1. 44 3-{[4-(4-Acetyl-3- hydroxy-2-iodo- phenoxymethyl)-phenyl]-hydroxy- methyl}-benzoic acid

¹H NMR (DMSO-d₆) δ 7.97-7.90 (m, 2 H), 7.77-7.71 (m, 1 H), 7.57-7.50 (m,1 H), 7.46-7.32 (m, 5 H), 6.72 (d, J = 8.8 Hz, 1 H), 5.75 (s, 1 H), 5.27(s, 2 H), 2.58 (s, 3 H); MS (m/e): 517 (M − 1).

Preparation 64 Synthesis of 2-fluoro-5-formyl-benzonitrile

Add freshly ground magnesium (1.72 g, 70.7 mmol) to a solution of5-chloro-2-fluoro-benzonitrile (10.0 g, 64.3 mmol) andN,N-dimethylformamide (5.64 g, 77.1 mmol) in tetrahydrofuran (0.2 M).Add iodine (0.816 g, 3.21 mmol). Heat the solution at reflux for 6 h.Quench the reaction with 1N hydrochloric acid and extract the mixturewith ethyl acetate (3×). Dry the combined organic layers with sodiumsulfate and concentrate to afford the title compound (9.20 g, 61.7 mmol,96%): ¹H NMR (CDC₁₃, 400 MHz) δ 7.15 (m, 1H), 7.59 (m, 1H), 7.66 (m,1H), 10.4 (s, 1H).

Preparation 65 Synthesis of5-{[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-hydroxy-methyl}-2-fluoro-benzonitrile

Add freshly ground magnesium (0.887 g, 36.5 mmol) to a solution of(4-bromo-benzyloxy)-tert-butyl-dimethyl-silane (10.0 g, 33.2 mmol) intetrahydrofuran (0.2 M). Add iodine (0.400 g, 1.50 mmol). Heat thesolution at reflux for 6 h. Add 2-fluoro-5-formyl-benzonitrile (4.95 g,33.2 mmol) at −40° C. and stir the reaction for 18 h while warming thereaction to room temperature. Quench the reaction with ammonium chloride(sat) and extract the mixture with ethyl acetate (3×). Dry the combinedorganic layers with sodium sulfate and concentrate. Purify the residuewith flash chromatography, eluting with hexanes, ramping to 50% ethylacetate/hexanes to elute the title compound (8.60 g, 23.1 mmol, 70%): ¹HNMR (400 MHz, CDC₁₃) δ 0.10 (s, 6H), 0.94 (s, 9H), 4.73 (s, 2H), 5.81(m, 1H), 7.15 (t, J=8.6 Hz, 1H), 7.27 (d, J=10.9 Hz, 2H), 7.33 (d, J=8.2Hz, 2H), 7.57 (m, 1H), 7.65 (m, 1H).

Preparation 66 Synthesis of5-[[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-fluoro-benzonitrile

Add 3,4-dihydro-2H-pyran (0.340 g, 4.04 mmol) to a solution of5-{[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-hydroxy-methyl}-2-fluoro-benzonitrile(1.00 g, 2.69 mmol) and pyridinium-toluenesulfonate (0.068 g, 0.269mmol) in dichloromethane (0.2M). Stir the reaction for 3 h at roomtemperature. Evaporate solvent and filter through a short pad of silicagel. The title compound (1.20 g, 2.63 mmol, 98%) is taken directly ontothe next step (Preparation 58). MS (m/z): 456 (M+1).

Preparation 67 Synthesis of2-fluoro-5-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

Add tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 5.27 mL, 5.27mmol) to5-[[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-fluoro-benzonitrile(1.20 g, 2.64 mmol) and stir the solution overnight. Dilute withdichloromethane and wash with water and brine. Dry the organic layer andconcentrate the solution to afford the title compound (0.890 g, 2.60mmol, 99%, mixture of diastereomers): ¹H NMR (400 MHz, CDC₁₃) δ 1.55 (m,2H), 1.68 (m, 2H), 1.74 (m, 2H), 3.46 (m, 1H), 3.77 (m, 1H), 4.60 (m,1H), 4.67 (s, 2H), 5.78 (s, 1H), 7.10 (m, 1H), 7.27 (m, 4H), 7.55 (m,1H), 7.64 (m, 1H).

Preparation 68 Synthesis of5-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-fluoro-benzonitrile

Employing the method as described essentially in Preparation 14 using2-fluoro-5-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(1.00 g, 2.93 mmol), the title compound is obtained (0.400 g, 0.773mmol, 26%): MS (m/z): 516 (M−1).

Preparation 69 Synthesis of1-(4-{4-[[4-fluoro-3-(2H-tetrazol-5-yl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-2-hydroxy-3-propyl-phenyl)-ethanone

Employing the method described essentially in Example 1 using5-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-fluoro-benzonitrile(0.400 g, 0.773 mmol), the title compound was obtained (0.120 g, 0.214mmol, 28%): MS (m/z): 559 (M−1).

Example 45 Synthesis of1-[4-(4-{[4-fluoro-3-(2H-tetrazol-5-yl)-phenyl]-hydroxy-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone

Add p-toluenesulfonic acid (2.00 mg, 0.012 mmol) to a solution of1-(4-{4-[[4-fluoro-3-(2H-tetrazol-5-yl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-2-hydroxy-3-propyl-phenyl)-ethanone(0.130 g, 0.232 mmol) in methanol (0.2 M) and stir for 24 h. Evaporatesolvent and filter through a pad of silica gel to afford the titlecompound (0.100 g, 0.220 mmol, 91%): MS (m/z): 475 (M−1).

Example 46 Synthesis of1-[4-(4-{[4-fluoro-3-(2Na-tetrazol-5-yl)-phenyl]-hydroxy-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanonesodium salt

Add excess sodium methoxide 0.5 M solution in methanol) to a solution of1-[4-(4-{[4-fluoro-3-(2H-tetrazol-5-yl)-phenyl]-hydroxy-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone,and stir for 30 min. Evaporate solvent. Add 1:10 tetrahydrofuran/etherand soniccate the residue. Filter and collect the solid product. Thetitle compound is obtained: ¹H NMR (400 MHz, DMSO-d₆) δ 0.86 (t, J=7.4Hz, 3H), 1.45-1.50 (m, 2H), 2.56 (s, 3H), 3.37-3.39 (m, 2H), 5.21 (s,2H), 5.74 (s, 1H), 6.70 (d, J=9.0 Hz, 1H), 7.11-7.15 (m, 1H), 7.29 (brs, 1H), 7.37 (m, 4H), 7.78 (d, J=9.0 Hz, 1H), 7.91 (d, J=6.6 Hz, 1H),12.8 (s, 1H). MS (m/z): 475 (M−1).

Preparation 70 Synthesis of 5-formyl-2-methoxy-benzonitrile

Add copper (I) cyanide (4.58 g, 51.2 mmol) to a solution of3-bromo-4-methoxy-benzaldehyde (10.0 g, 46.5 mmol) inN,N-dimethylformamide (0.2 M). Heat the solution to 120° C. and stir thesolution for 1d. Quench with potassium carbonate (sat) and extract withdiethyl ether (5×). Wash organic layers with water, dry with sodiumsulfate, and concentrate to afford the title compound (5.00 g, 31.0mmol, 67%): ¹H NMR (400 MHz, DMSO-d₆) δ 4.04 (s, 3H), 7.47 (d, J=8.6 Hz,1H), 8.20 (m, 1H), 8.33 (m, 1H), 9.91 (s, 1H).

Preparation 71 Synthesis of5-{[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-hydroxy-methyl}-2-methoxy-benzonitrile

The title compound is prepared essentially as described in Preparation65 employing 5-formyl-2-methoxy-benzonitrile (2.67 g, 16.6 mmol) and(4-bromo-benzyloxy)-tert-butyl-dimethyl-silane (5.00 g, 16.6 mmol), thetitle compound is obtained (3.50 g, 9.12 mmol, 55%): ¹H NMR (400 MHz,CDC₁₃) δ 0.10 (s, 6H), 0.94 (s, 9H), 4.66 (s, 2H), 5.78 (m, 1H), 6.96(m, 1H), 7.27 (m, 4H), 7.53 (m, 2H).

Preparation 72 Synthesis of5-[[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzonitrile

The title compound is prepared essentially as described in Preparation66 employing5-{[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-hydroxy-methyl}-2-methoxy-benzonitrile(2.00 g, 5.21 mmol), the title compound is obtained (2.44 g, 5.21 mmol,99%): MS (m/z): 468 (M+1).

Preparation 73 Synthesis of5-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzonitrile

The title compound is prepared essentially as described in Preparation67 employing5-[[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzonitrile(2.44 g, 5.22 mmol), the title compound is obtained (1.60 g, 4.53 mmol,87%, mixture of diastereomers): ¹H NMR (400 MHz, CDC₁₃) δ 1.55 (m, 2H),1.68 (m, 2H), 1.84 (m, 2H), 3.49 (m, 1H), 3.81 (m, 1H), 3.93 (s, 3H),4.60 (m, 1H), 4.65 (s, 2H), 5.79 (s, 1H), 6.85 (m, 1H), 7.35 (m, 4H),7.50 (m, 1H), 7.59 (m, 1H).

Preparation 74 Synthesis of5-[[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzonitrile

The title compound is prepared essentially as described in Preparation68 employing5-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzonitrile(1.60 g, 4.53 mmol), the title compound is obtained (2.28 g, 4.83 mmol,95%, mixture of diastereomers): MS (m/z): 528 (M−1).

Preparation 75 Synthesis of1-(2-hydroxy-4-{4-[[4-methoxy-3-(2H-tetrazol-5-yl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-3-propyl-phenyl)-ethanone

Using the method of tetrazole formation described in Example 1 with5-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzonitrile(1.00 g, 1.89 mmol), the title compound is obtained (0.620 g, 1.10 mmol,58%): MS (m/z): 571 (M−1).

Preparation 76 Synthesis of1-[2-hydroxy-4-(4-{(tetrahydro-pyran-2-yloxy)-[3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-3-trifluoromethyl-phenyl]-ethanone

Employing the procedure of Example 1 using3-[[4-(4-acetyl-3-hydroxy-2-trifluoromethyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(384 mg, 0.731 mmol), sodium azide (475 mg, 7.31 mmol), andtriethylamine hydrochloride (1.01 g, 7.31 mmol) to yield the titlecompound as a tan solid (400 mg, 96%): ¹H NMR (CD₃CN) 61.44-1.91 (m,6H), 2.56 (s, 3H), 3.44 (m, 1H), 3.78 (m, 1H), 4.66 (q, 1H), 5.23 (d,2H), 5.91 (d, 1H), 6.73 (dd, 1H), 7.39-7.62 (m, 5H), 7.89-8.08 (m, 3H),13.75 (s, 1H).

Preparation 77 Synthesis of1-[3-ethyl-2-hydroxy-4-(4-{(tetrahydro-pyran-2-yloxy)-[3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-phenyl]-ethanone

Employing the procedure of Example 1 using3-[[4-(4-acetyl-2-ethyl-3-hydroxy-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(869 mg, 1.79 mmol), sodium azide (1.16 g, 17.9 mmol), and triethylaminehydrochloride (2.46 g, 17.9 mmol), the title product is obtained as aclear oil (900 mg, 66%): MS (esi negative) m/z (rel intensity) 527(100).

Example 47 Synthesis of1-[2-hydroxy-4-(4-{hydroxy-[4-methoxy-3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-3-propyl-phenyl]-ethanone

The title compound is prepared essentially as described in Example 45employing1-(2-hydroxy-4-{4-[[4-methoxy-3-(2H-tetrazol-5-yl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-3-propyl-phenyl)-ethanone(0.620 g, 1.10 mmol) to afford the title compound (0.350 g, 0.700 mmol,72%): ¹H NMR (400 MHz, DMSO-d₆) δ 0.86 (t, J=7.4 Hz, 3H), 1.47 (m, 2H),2.50 (m, 2H), 2.56 (s, 3H), 3.94 (s, 3H), 5.21 (s, 2H), 5.78 (s, 1H),6.70 (d, J=9.4 Hz, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.39 (d, J=8.2 Hz, 2H),7.43 (d, J=8.2 Hz, 2H), 7.56 (q, J=7.0 Hz, 1H), 7.78 (d, J=9.0 Hz, 1H),8.12 (d, J=2.3 Hz, 1H), 12.83 (s, 1H). MS (m/z): 487 (M−1).

Preparation 78 Synthesis of5-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzoicacid

Heat a solution of5-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzonitrile(0.650 g, 1.23 mmol) and potassium hydroxide (1.38 g, 24.6 mmol) inethanol (0.2 M) at reflux for 96 h. Evaporate solvent, acidify with 1Nhydrochloric acid, then extract with dichloromethane (5×). Dry thecombined organic layers and concentrate to afford the title compound(0.600 g, 1.09 mmol, 89%): MS (m/z): 547 (M−1).

Preparation 79 Synthesis of5-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzamide

Add N,N-diisopropylcarbodiimide (0.114 g, 0.902 mmol) to a solution of5-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzoicacid (0.450 g, 0.820 mmol) and 1-hydroxybenzotriazole hydrate (0.122 g,0.902 mmol) in dichloromethane (0.2M). Stir the solution for 1 h at roomtemperature. Saturate the solution with ammonia gas and stir thesolution for 24 h. Collect the precipitate as the title compound (0.440g, 0.815 mmol, 98%): MS (m/z): 546 (M−1).

Example 48 Synthesis of1-[2-hydroxy-4-(4-{hydroxy-[4-methoxy-3-(2Na-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-3-propyl-phenyl]-ethanonesodium salt

Employing the general method 3 with1-[2-hydroxy-4-(4-{hydroxy-[4-methoxy-3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-3-propyl-phenyl]-ethanone(0.200 g, 0.409 mmol), the title compound is obtained (0.190 g, 0.372mmol, 91%): ¹H NMR (400 MHz, DMSO-d₆) δ 0.86 (t, J=7.4 Hz, 3H), 1.47 (m,2H), 2.50 (s, 3H), 2.56 (m, 2H), 3.70 (s, 3H), 5.16 (s, 2H), 5.67 (s,1H), 5.80 (br s, 1H), 6.54 (br s, 1H), 6.96 (d, J=8.6 Hz, 1H), 7.26 (q,J=7.2 Hz, 1H), 7.35 (d, J=7.8 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.56 (d,J=2.3 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 12.76 (br s, 1H). MS (m/z): 487(M−1).

Preparation 80 Synthesis of3-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-benzonitrile

Stir a solution of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile(110 mg, 0.264 mmol) in dichloromethane (5 mL) at 0° C. Add Dess-Martinperiodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (H)-one)(120 mg, 0.29 mmol) and stir the reaction for 1.5 hr at roomtemperature. Dilute the reaction mixture with aqueous saturated sodiumbicarbonate (50 mL) and extract with ethyl acetate (3×50 mL). Dry thecombined extracts over sodium sulfate, filter and concentrate. Purifythe residue via silica gel chromatography, eluting with 7:3hexanes:ethyl acetate to afford the title compound as a white solid (105mg, 95%). Mass spectrum (M+H) 414.

Example 49 Synthesis of1-(2-hydroxy-3-propyl-4-{4-[3-(1H-tetrazol-5-yl)-benzoyl]-benzyloxy}-phenyl)-ethanone

The title compound is prepared essentially as described for1-[4-(4-{fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone.The tile compound is isolated as a tan solid, 115 mg, 99%. ¹H NMR(DMSO-d₆) δ 12.89 (s, 1H), 8.42 (s, 1H), 8.36 (d, 1H), 7.95 (d, 1H),7.80-7.89 (m, 4H), 7.68 (d, 2H), 6.76 (d, 1H), 5.42 (s, 2H), 2.66 (t,2H), 2.60 (s, 3H), 1.54 (q, 2H), 0.92 (t, 3H). LC/MS M−1 455.

Example 50 Synthesis of3-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-benzoic acid

The title compound is prepared essentially as described for3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoicacid employing3-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-benzonitrile,to give the title compound (52 mg, 100%), as a white powder. ¹H NMR(DMSO-d₆) δ 13.34 (bs, 1H), 12.89 (s, 1H), 8.22-8.26 (m, 2H), 8.01 (d,1H), 7.82-7.87 (m, 3H), 7.75 (t, 1H), 7.65-7.68 (m, 2H), 6.75 (d, 1H),5.42 (s, 2H), 2.60-2.68 (m, 5H), 1.50-1.55 (m, 2H), 0.91 (t, 3H). LCMSM−1 431.

Preparation 81 Synthesis of 5-bromo-N-methoxy-N-methyl-nicotinamide

Heat a solution of 5-bromo-nicotinic acid (50 g, 248 mmol) in thionylchloride (200 mL) to reflux. After 4 hours, cool to ambient temperatureand concentrate under reduced pressure to give a residue. Dissolveresidue in dichloromethane (1.0 L). Add pyridine (58.7 g, 743 mmol)followed by O,N-dimethyl-hydroxylamine hydrochloride (26.6 g, 272 mmol)and stir. After 18 hours add water (1.0 L) and extract withdichloromethane. Combine organic layers, dry with sodium sulfate, filterand concentrate under reduced pressure to yield the title compound as aclear oil (59.1 g, 97%):¹H NMR (DMSO-d₆) δ 3.29 (bs, 3H), 3.57 (bs, 3H),8.24 (dd, 1H), 8.75 (d, 1H), 8.83 (d, 1H).

Preparation 82 Synthesis of(5-bromo-pyridin-3-yl)-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-methanone

Add n-butyllithium (4.56 mL, 7.30 mmol) to a solution of(4-bromo-benzyloxy)-tert-butyl-dimethyl-silane (2.0 g, 6.64 mmol) intetrahydrofuran (60 mL) cooled to −78° C. After 2 hours, add5-bromo-N-methoxy-N-methyl-nicotinamide (1.63 g, 6.64 mmol), and allowsolution to warm gradually to ambient temperature. After 2 hours, add 1%aqueous hydrochloric acid (60 mL) and stir. After 20 minutes, extractsolution with ethyl acetate. Combine organic layers, dry over sodiumsulfate, filter and concentrate under reduced pressure to give aresidue. Purify the residue by flash chromatography eluting with 12.5%ethyl acetate:hexanes to yield the title compound as a white solid (1.10g, 41%): ¹H NMR (DMSO-d₆) δ 0.11 (s, 6H), 0.93 (s, 9H), 4.84 (bs, 2H),7.52 (d, 2H), 7.79 (d, 2H), 8.31 (t, 1H), 8.82 (d, 1H), 8.98 (d, 1H).

Preparation 83 Synthesis of5-[4-(tert-butyl-dimethyl-silanyloxymethyl)-benzoyl]-nicotinonitrile

Add tetrakis(triphenylphosphine)palladium (284 mg, 0.246 mmol) to asolution of(5-bromo-pyridin-3-yl)-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-methanone(1.0 g, 2.46 mmol) and zinc cyanide (578 mg, 4.92 mmol) indimethylformamide (25 mL) and stir. Purge solution with nitrogen andheat to 80° C. After 18 hours, add water (100 mL) and extract with ethylacetate. Combine organic layers, dry over sodium sulfate, filter andconcentrate under reduced pressure to give a residue. Purify the residuewith flash chromatography eluting with 12.5% ethyl acetate:hexanes toyield the title compound as a white solid (550 mg, 63%): ¹H NMR(DMSO-d₆) δ 0.11 (s, 6H), 0.93 (s, 9H), 4.84 (bs, 2H), 7.53 (d, 2H),7.83 (d, 2H), 8.61 (t, 1H), 9.09 (d, 1H), 9.26 (d, 1H).

Preparation 84 Synthesis of 5-(4-hydroxymethyl-benzoyl)-nicotinonitrile

Dissolve5-[4-(tert-butyl-dimethyl-silanyloxymethyl)-benzoyl]-nicotinonitrile(510 mg, 1.45 mmol) in 10% aqueous hydrochloric acid (10 mL) andtetrahydrofuran (50 mL) and stir. After 1 hour, add saturated aqueoussodium bicarbonate (50 mL) and extract with ethyl acetate. Combineorganic layers, dry over sodium sulfate, filter and concentrate underreduced pressure to yield the title compound as a white solid (325 mg,94%): ¹H NMR (DMSO-d₆) δ 4.64 (d, 2H), 5.44 (t, 1H), 7.53 (d, 2H), 7.80(d, 2H), 8.59 (t, 1H), 9.09 (d, 1H), 9.27 (d, 1H).

Preparation 85 Synthesis of5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinonitrile

The title compound is prepared essentially as described in Preparation14 employing 5-(4-hydroxymethyl-benzoyl)-nicotinonitrile (325 mg, 1.36mmol) to afford the title compound as a white solid (448 mg, 79%): ¹HNMR (DMSO-d₆) δ 0.90 (t, 3H), 1.52 (sextet, 2H), 2.58 (s, 3H), 2.64 (t,2H), 5.41 (bs, 2H), 6.74 (d, 1H), 7.66 (d, 2H), 7.83 (d, 1H), 7.89 (d,2H), 8.62 (t, 1H), 9.11 (d, 1H), 9.27 (d, 1H), 12.86 (s, 1H).

Example 51 Synthesis of1-(2-hydroxy-3-propyl-4-{4-[5-(2H-tetrazol-5-yl)-pyridine-3-carbonyl]-benzyloxy}-phenyl)-ethanone

The title compound is prepared essentially as described in Example 1using5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinonitrile(448 mg, 1.08 mmol), sodium azide (703 mg, 10.8 mmol), and triethylaminehydrochloride (1.49 g, 10.8 mmol) to yield the title product as a whitesolid (338 mg, 66%): ¹H NMR (DMSO-d₆) δ 0.90 (t, 3H), 1.53 (sextet, 2H),2.59 (s, 3H), 2.64 (t, 2H), 5.43 (s, 2H), 6.76 (d, 1H), 7.67 (d, 2H),7.84 (d, 1H), 7.92 (d, 2H), 8.68 (t, 1H), 9.05 (d, 1H), 9.46 (d, 1H),12.86 (s, 1H); MS (esi negative) m/z (rel intensity) 456 (100).

Example 52 Synthesis of5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinic acid

Add lithium hydroxide (289 mg, 12.06 mmol) to a solution of5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinonitrile(500 mg, 1.21 mmol) in dioxane (10 mL) and water (10 mL) and stir. Heatsolution to reflux. After 1 hour cool to ambient temperature, add water(100 mL) and wash with ethyl acetate. Acidify with 10% aqueoushydrochloric acid (15 mL), and extract with ethyl acetate. Combineorganic layers, dry with sodium sulfate, filter and concentrate underreduced pressure to give a residue. Purify residue by sonicating inether for 1 hour. Filter the resulting precipitate to yield the titlecompound as a beige solid (262 mg, 50%): ¹H NMR (DMSO-d₆) δ 0.86 (t,3H), 1.48 (sextet, 2H), 2.54 (s, 3H), 2.59 (t, 2H), 5.38 (s, 2H), 6.70(d, 1H), 7.62 (d, 2H), 7.79 (d, 1H), 7.84 (d, 2H), 8.42 (s, 1H), 9.05(s, 1H), 9.24 (s, 1H), 12.82 (s, 1H), 13.72 (bs, 1H); MS (esi negative)m/z (rel intensity) 432 (100).

Preparation 86 Synthesis of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-fluoro-methyl}-benzonitrile

A solution of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile(5.0 g, 12.06 mmol) and dichloromethane (100 mL) is stirred at −78° C.Diethylaminosulfur trifluoride (1.8 mL, 13.74 mmol) is added, the coldbath is removed, and the reaction is stirred at room temperature 1 hr.The reaction mixture is diluted with water (100 mL), the layers areseparated, and the aqueous layer is extracted with dichloromethane(2×100 mL). The organic layers are combined, washed with water (50 mL),dried over magnesium sulfate, filtered, and concentrated to give 5.1 g,100%, of the title compound as a tan solid. LCMS M+1=418.

Example 53 Synthesis of1-[4-(4-{fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone

A mixture of3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-fluoro-methyl}-benzonitrile(4.7 g, 11.26 mmol), zinc (II) bromide (10.1 g, 45 mmol), sodium azide(5.85 g, 90 mmol), and N-methylpyrrolidinone (50 ml) is heated to 140°C. and stirred 1 hr. The reaction is cooled to room temperature anddiluted with water (200 mL). The pH is adjusted to 2 with 5N aqueoushydrochloric acid and extracted with ethyl acetate (3×100 mL). Theextracts are combined, dried over magnesium sulfate, filtered, andconcentrated. The residue is purified via reversed phase C18chromatography eluting with 4:6 acetonitrile: (0.1% trifluoroaceticacid) water to 7:3 acetonitrile:(0.1% trifluoroacetic acid) water in 8runs to give 3.08 g, 59%, of the title compound as fine white needles.¹H NMR (DMSO-d₆) δ 12.86 (s, 1H), 8.13 (s, 1H), 8.03 (d, 1H), 7.81 (d,1H), 7.61-7.70 (m, 2H), 7.48 (m, 4H), 6.78-6.93 (d, 1H), 6.72 (d, 1H),5.29 (s, 2H), 2.58-2.63 (m, 5H), 1.46-1.53 (m, 2H), 0.88 (t, 3H). LCMSM−1 459.

Example 54 Synthesis of1-[4-(4-{azido-[3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone

The title compound is obtained as an additional product in thepurification of Example531-[4-(4-{fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone,as a white solid, 340 mg, 7%. ¹H NMR (DMSO-d₆) δ 12.86 (s, 1H), 8.11 (s,1H), 7.99 (d, 1H), 7.80 (d, 1H), 7.59-7.68 (m, 2H), 7.45-7.51 (m, 4H),6.73 (d, 1H), 6.32 (s, 1H), 5.28 (2H), 2.58-2.62 (m, 5H), 1.45-1.53 (m,2H), 0.87 (t, 3H). LC/MS M−1 482.

Preparation 87 Synthesis of3-{[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-fluoro-methyl}-benzonitrile

A mixture of3-{[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile(0.5 g, 1.29 mmol) and dichloromethane (15 mL) is stirred at −78° C.Diethylaminosulfur trifluoride (0.2 mL, 1.48 mmol) is added and thereaction is warmed to room temperature and stirred 30 min. The mixtureis cooled to 0° C. and diluted with water (50 mL). The layers areseparated, and the aqueous layer is extracted with dichloromethane (3×50mL). The organic layers are combined, dried on magnesium sulfate,filtered, and concentrated. The residue is purified via silicachromatography eluting with hexanes to 7:3 hexanes:ethyl acetate to givethe title compound (400 mg, 80%) as a white solid. LCMS M+1 390.

Example 55 Synthesis of1-[4-(4-{fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-methyl-phenyl]-ethanone

A mixture of3-{[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-fluoro-methyl}-benzonitrile(400 mg, 1.03 mmol), zinc (II) bromide (280 mg, 1.24 mmol), sodium azide(160 mg, 2.48 mmol) and N-methylpyrrolidinone (10 mL) is stirred at 140°C. 1 hr. The reaction mixture is cooled, diluted with water, and the pHis adjusted to 2 with aqueous hydrochloric acid. The product isextracted with ethyl acetate, dried over magnesium sulfate, filtered,and concentrated. The residue is purified via reversed phase C-18chromatography eluting with 4:6 acetonitrile:(0.1% trifluoroacetic acid)water to acetonitrile to give the title compound (100 mg, 22%) as awhite solid. ¹H NMR (DMSO-d₆) δ 12.85 (s, 1H), 8.13 (s, 1H), 8.03 (d,1H), 7.80 (d, 1H), 7.6107.70 (m, 2H), 7.48-7.55 (m, 4H), 6.78-6.94 (d,1H), 6.73 (d, 1H), 5.29 (s, 2H), 2.59 (s, 3H), 2.05 (s, 3H). LCMS M−1431.

Example 56 Synthesis of3-{[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-fluoro-methyl}-benzoicacid

A suspension of3-{[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoicacid (100 mg, 0.246 mmol) and dichloromethane (5 mL) is stirred at −78°C. Dimethylamino sulfur trifluoride (35 μL, 0.271 mmol) is added and themixture is warmed to room temperature. An additional portion ofdimethylamino sulfur trifluoride (35 μL, 0.271 mmol) is added andsuspension becomes a solution. The reaction mixture is diluted withaqueous 2N sodium hydroxide (5 mL) and tetrahydrofuran (2 mL) andstirred 10 min. The pH is adjusted to 2 with aqueous 5N hydrochloricacid and extracted with ethyl acetate (2×20 mL). The combined extractsare concentrated and the resulting residue is purified via silicachromatography eluting with hexanes to 1:1 hexanes:ethyl acetate to givethe title compound (70 mg, 70%) as a white solid. ¹H NMR (DMSO-d₆) δ13.12 (s, 1H), 12.86 (s, 1H), 7.93-7.95 (m, 2H), 7.82 (d, 1H), 7.68 (d,1H), 7.44-7.59 (m, 5H), 6.75-6.90 (d, 1H), 6.72 (d, 1H), 5.29 (s, 2H),2.59 (s, 3H), 2.06 (s, 3H). LCMS M−1 407.

Preparation 88 Synthesis of3-[4-(4-acetyl-3-hydroxy-2-trifluoromethyl-phenoxymethyl)-benzyl]-benzonitrile

To3-{[4-(4-acetyl-3-hydroxy-2-trifluoromethyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile(211 mg, 0.48 mmol) in anhydrous CH₂Cl₂ (5 mL) at room temperature underAr is added Et₃SiH (0.61 mL, 3.8 mmol) and BF₃ ether complex (0.12 mL,0.96 mmol). The reaction mixture is stirred at room temperature for 2 hand quenched into saturated aqueous NH₄Cl (20 mL). The aqueous mixtureis extracted with CH₂Cl₂ (3×25 mL). The organic layers are combined,washed with brine, dried over sodium sulfatesodium sulfate, andconcentrated. The residue is purified by flash column chromatographyusing 50% ethyl acetate/hexane as eluent to give the title compound (108mg, 53%). LC-MS (m/e): 424 (M−1).

Example 57 Synthesis of1-(2-hydroxy-4-{4-[3-(2H-tetrazol-5-yl)-benzyl]-benzyloxy}-3-trifluoromethyl-phenyl)-ethanone

The title compound is prepared essentially as described for1-(2-hydroxy-4-{4-[3-(2H-tetrazol-5-yl)-phenoxy]-benzyloxy}-3-trifluoromethyl-phenyl)-ethanoneemploying3-[4-(4-acetyl-3-hydroxy-2-trifluoromethyl-phenoxymethyl)-benzyl]-benzonitrile(58%). LC-MS (m/e): 467 (M−1); ¹H NMR (DMSO-d₆) δ 13.79 (1H, s), 8.21(1H, d), 7.80-8.00 (2H, m), 7.30-7.60 (6H, m), 6.92 (1H, d), 5.35 (2H,s), 4.08 (2H, s), 2.65 (3H, s).

Example 58 Synthesis of1-(2-hydroxy-3-isopropyl-4-{4-[3-(2H-tetrazol-5-yl)-benzyl]-benzyloxy}-phenyl)-ethanone

To1-[2-Hydroxy-4-(4-{hydroxy-[3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-3-isopropyl-phenyl]-ethanone(100 mg, 0.22 mmol) in anhydrous CH₂Cl₂ (5.4 mL) is added Et₃SiH (281μL, 1.76 mmol) and BF₃.ether complex (56 μL, 0.44 mmol). The reactionmixture is stirred for 1.5 h. The reaction mixture is quenched intosaturated aqueous NH₄Cl (10 mL) and extracted with a 50%tetrahydrofuran/ethyl acetate solution (3×30 mL). The organic layers arecombined, washed with brine, dried over sodium sulfatesodium sulfate,and concentrated to an oil. The residue is purified by reverse phaseHPLC using a gradient of 90:10 to 20:80 (H₂O/0.1% TFA):CH₃CN as eluentto give the title compound (29 mg, 30%). LC-MS (m/e): 441 (M−1); ¹H NMR(DMSO-d₆) δ 13.1 (1H, s), 7.82-8.00 (2H, m), 7.78 (1H, d), 7.30-7.55(6H, m), 6.72 (1H, d), 5.22 (2H, s), 4.08 (2H, s), 3.57 (1H, m), 2.57(3H, s), 1.26 (3H, s), 1.23 (3H, s).

Example 59 Synthesis of1-(3-fluoro-2-hydroxy-4-{4-[3-(2H-tetrazol-5-yl)-benzyl]-benzyloxy}-phenyl)-ethanone

The title compound is prepared essentially as described in Example 57employing1-[3-fluoro-2-hydroxy-4-(4-{hydroxy-[3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-phenyl]-ethanoneand stirring 2 h at room temperature. Obtained is the title compound (18mg, 27%). LC-MS (m/e): 417 (M−1); ¹H NMR (DMSO-d₆) δ 12.34 (1H, s),7.82-8.00 (2H, m), 7.73 (1H, dd), 7.47-7.60 (2H, m), 7.42 (2H, d), 7.34(2H, d), 6.89 (1H, dd), 5.28 (2H, s), 4.08 (2H, s), 2.61 (3H, s).

Example 60 Synthesis of1-(2-hydroxy-3-propyl-4-{4-[3-(1H-tetrazol-5-yl)-benzyl]-benzyloxy}-phenyl)-ethanone

The title compound is prepared in a similar manner to1-[4-(4-{fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanoneemploying3-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzyl]-benzonitrile.The crude product is purified via reversed phase C18 preparativechromatography over 8 runs to provide the title compound as a tan solid(6.3 g, 58%). ¹H NMR (DMSO-d₆) δ 12.86 (s, 1H), 7.96 (s, 1H), 7.86-7.89(m, 1H), 7.81 (d, 1H), 7.48-7.58 (m, 2H), 7.33-7.42 (m, 4H), 6.73 (d,1H), 5.23 (s, 2H), 4.08 (s, 2H), 2.56-2.61 (m, 5H), 1.45-1.53 (m, 2H),0.88 (t, 3H). LCMS M−1 441.

Example 61 Synthesis of3-[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-benzyl]-benzoic acid

A solution of3-{[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoicacid (80 mg, 0.197 mmol), triethylsilane (250 μL, 1.57 mmol), borontrifluoride diethyl etherate (70 μL, 0.542 mmol), and dichloromethane (2mL) is stirred 1 hr at room temperature. The mixture is diluted withwater and extracted with ethyl acetate (2×10 mL). The combined extractsare dried over magnesium sulfate, filtered and concentrated. The residueis recrystallized from dichloromethane/hexanes to give (54 mg, 70%) thetitle compound, as a white solid. ¹H NMR (DMSO-d₆) δ 12.92 (bs, 1H),12.85 (s, 1H), 7.78-7.82 (m, 3H), 7.27-7.49 (m, 6H), 6.72 (d, 1H), 5.23(s, 2H), 4.06 (s, 2H), 2.52 (s, 3H), 2.04 (s, 3H). LCMS M−1 389.

The following compounds are prepared essentially as described forExample 61.

Ex. No. Chemical name Structure Physical data 623-[4-(3-Hydroxy-2-methyl- 4-propionyl- phenoxymethyl)-benzyl]- benzoicacid

¹H NMR (DMSO-d₆) δ 12.92 (bs, 1 H), 12.91 (s, 1 H), 7.77-7.85 (m, 3 H),7.28-7.60 (m, 5 H), 7.15 (s, 1 H), 6.72 (d, 1 H), 5.22 (s, 2 H), 4.04(s, 2 H), 3.02-3.09 (m, 2 H), 2.04 (s, 3 H), 1.08 (t, 3 H). LCMS M − 1403. 63 3-[4-(4-Acetyl-3-hydroxy-2- isopropyl-phenoxymethyl)-benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.06 (s, 1 H), 12.92 (s, 1 H), 7.78-7.82 (m, 3 H),7.51-7.52 (m, 1 H), 7.39-7.46 (m, 3 H), 7.29-7.32 (m, 2 H), 6.72 (d, 1H), 5.21 (s, 2 H), 4.05 (s, 2 H), 3.57 (m, 1 H), 2.58 (s, 3 H), 1.24 (d,6 H). LCMS M − 1 417. 64 3-[4-(2-Chloro-3-hydroxy- 4-propionyl-phenoxymethyl)-benzyl]- benzoic acid

¹H NMR (DMSO-d₆) δ 13.19 (s, 1 H), 12.92 (bs, 1 H), 7.96 (d, 1 H),7.77-7.82 (m, 2 H), 7.53-7.55 (m, 1 H), 7.40-7.46 (m, 3 H), 7.29-7.32(m, 2 H), 6.89 (d, 1 H), 5.32 (s, 2 H), 4.05 (s, 2 H), 3.06-3.14 (m, 2H), 1.11 (t, 3 H). LCMS M − 1 423. 65 3-[4-(4-Acetyl-2-chloro-3-hydroxy-phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.15 (s, 1 H), 12.94 (bs, 1 H), 7.94 (d, 1 H),7.77-7.82 (m, 2 H), 7.30-7.51 (m, 6 H), 6.91 (d, 1 H), 5.33 (s, 2 H),4.05 (s, 2 H), 2.63 (s, 3 H). LCMS M − 1 409. 663-[3-(4-Acetyl-3-hydroxy-2- methyl-phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 12.92 (bs, 1 H), 12.85 (s, 1 H), 7.78-7.82 (m, 3 H),7.27-7.49 (m, 6 H), 6.72 (d, 1 H), 5.23 (s, 2 H), 4.06 (s, 2 H), 2.59(s, 3 H), 2.01 (s, 3 H). LCMS M − 1 389. 67 3-[3-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 12.92 (bs, 1 H), 12.85 (s, 1 H), 7.78-7.82 (m, 3 H),7.27-7.49 (m, 6 H), 6.72 (d, 1 H), 5.22 (s, 2 H), 4.05 (s, 2 H),2.53-2.59 (m, 5 H), 1.41-1.47 (m, 2 H), 0.83 (t, 3 H). LCMS M − 1 417.68 3-[3-(3-Hydroxy-2-methyl- 4-propionyl- phenoxymethyl)-benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 12.90 (bs, 1 H), 12.90 (s, 1 H), 7.78-7.82 (m, 3 H),7.27-7.49 (m, 6 H), 6.72 (d, 1 H), 5.23 (s, 2 H), 4.06 (s, 2 H),3.02-3.09 (m, 2 H), 2.01 (s, 3 H), 1.11 (t, 3 H). LCMS M − 1 403. 693-[3-(4-Acetyl-2-chloro-3- hydroxy-phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.15 (s, 1 H), 12.93 (bs, 1 H), 7.94 (d, 1 H),7.77-7.82 (m, 2 H), 7.25-7.46 (m, 6 H), 6.89 (d, 1 H), 5.33 (s, 2 H),2.63 (s, 3 H). LCMS M + 1 411.

Preparation 89 Synthesis of3-[methoxy-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile

A solution of3-[hydroxy-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile(0.64 g, 1.62 mmol) and tetrahydrofuran (10 mL) is stirred at 0° C.Sodium hydride, 60% in mineral oil, (80 mg, 1.95 mmol) is added and themixture is stirred at room temperature 10 min. The mixture is cooled to0° C. and iodomethane (0.12 mL, 1.8 mmol) is added. The resultingmixture is stirred at room temperature 18 hr. The mixture is dilutedwith aqueous saturated sodium hydrogen carbonate, extracted with ethylacetate, and the organic layer concentrated. The residue is purified viasilica chromatography eluting with hexanes to 9:1 hexanes:ethyl acetateto provide 400 mg, 60% the title compound, as a colorless oil. ¹H NMR(CDC₁₃) δ 7.70 (s, 1H), 7.55-7.69 (m, 2H), 7.27-7.46 (m, 5H), 5.27 (s,1H), 4.88 (s, 2H), 3.41 (s, 3H), 1.05-1.29 (m, 21H).

Preparation 90 Synthesis of3-[(4-hydroxymethyl-phenyl)-methoxy-methyl]-benzonitrile

A solution of3-[methoxy-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile(0.4 g, 0.976 mmol), tetrahydrofuran (10 mL) and a 1M tetrahydrofuransolution of tetrabutylammonium fluoride (1.2 mL, 1.2 mmol) is stirred atroom temperature 18 hr. The mixture is diluted with water (100 mL) andextracted with ethyl acetate (2×50 mL) and the combined extracts areconcentrated. The residue is purified via silica chromatography elutingwith hexanes to 1:1 hexanes:ethyl acetate to give the title compound(188 mg, 76%) as a colorless oil. LCMS M+1 254.

Preparation 91 Synthesis of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-methoxy-methyl}-benzonitrile

The title compound is prepared in a similar manner to3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrileemploying 3-[(4-Hydroxymethyl-phenyl)-methoxy-methyl]-benzonitrile toafford 248 mg, 78%, as a colorless oil. LCMS M+1 430.

Example 70 Synthesis of1-[2-hydroxy-4-(4-{methoxy-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-3-propyl-phenyl]-ethanone

The title compound is prepared essentially as described for1-[4-(4-{fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone,employing3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-methoxy-methyl}-benzonitrileto give (129 mg, 47%) of the title compound as a lavender foam. ¹H NMR(DMSO-d₆) δ 12.85 (s, 1H), 8.12 (s, 1H), 7.93 (m, 1H), 7.80 (d, 1H),7.59 (d, 2H), 7.42-7.49 (m, 4H), 6.71 (d, 1H), 5.50 (s, 1H), 5.25 (s,2H), 2.57-2.61 (m, 5H), 2.09 (s, 3H), 1.47-1.56 (m, 2H), 0.84-0.92 (m,3H). LCMS M−1 471.

Example 71 Synthesis of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-methoxy-methyl}-benzoicacid

The title compound is prepared essentially as described for3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoicacid employing3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-methoxy-methyl}-benzonitrileto give a white solid, 82%. ¹H NMR (DMSO-d₆) δ 13.00 (bs, 1H), 12.85 (s,1H), 7.96 (s, 1H), 7.79-7.85 (m, 2H), 7.63 (d, 1H), 7.40-7.48 (m, 5H),6.72 (d, 1H), 5.50 (s, 1H), 5.24 (s, 2H), 3.30 (s, 3H), 2.58-2.61 (m,5H), 1.44-1.52 (m, 2H), 0.84-0.88 (m, 3H). LCMS M+1 449.

Preparation 92 Synthesis of3-(4-triisopropylsilanyloxymethyl-benzoyl)-benzonitrile

A solution of3-[hydroxy-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile(2.06 g, 5.21 mmol), Dess-Martin periodinane(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(H)-one) (2.7 g, 6.25mmol), and dichloromethane (50 mL) is stirred at room temperature 24 hr.The mixture is diluted with aqueous saturated sodium hydrogen carbonateand extracted with dichloromethane (2×50 ml). The combined extracts aredried over magnesium sulfate, filtered, and concentrated. The residue ispurified via silica chromatography eluting with hexanes to 8:2hexanes:ethyl acetate to give the title compound (1.2 g, 60%) as a whitesolid. ¹H NMR (CDC₁₃) δ 8.06-8.10 (m, 2H), 7.89-7.91 (m, 1H), 7.79-7.81(m, 2H), 7.66 (t, 1H), 7.54-7.56 (m, 2H), 4.97 (s, 2H), 1.17-1.31 (m,21H).

Preparation 93 Synthesis of3-[1-(4-triisopropylsilanyloxymethyl-phenyl)-vinyl]-benzonitrile

A mixture of methyltriphenylphosphonium bromide (0.2 g, 0.56 mmol) andtetrahydrofuran (10 mL) is stirred at 0° C. Potassium tert-butoxide (72mg, 0.64 mmol) is added and the yellow solution is stirred 10 min atroom temperature. The solution is cooled to 0° C. and3-(4-Triisopropylsilanyloxymethyl-benzoyl)-benzonitrile (0.2 g, 0.51mmol) is added. The resulting orange reaction is stirred 1 hr at roomtemperature. The reaction is diluted with water and extracted with ethylacetate (2×50 mL). The extracts are combined, dried on magnesiumsulfate, filtered, and concentrated. The residue is purified via silicachromatography eluting with hexanes to 9:1 hexanes:ethyl acetate to give90 mg, 45%, as a colorless wax. ¹H NMR (CDC₁₃) δ 7.60-7.67 (m, 3H), 7.47(t, 1H), 7.37-7.40 (m, 2H) 7.27-7.28 (2H), 5.60 (s, 1H), 5.50 (s, 1H),1.10-1.29 (m, 21H).

Preparation 94 Synthesis of3-{1-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-vinyl}-benzonitrile

The title compound is prepared in a similar manner as3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile,employing3-[1-(4-triisopropylsilanyloxymethyl-phenyl)-vinyl]-benzonitrile to give0.46 g, 47%, of the title compound as a white solid. LCMS M+1 412.

Example 72 Synthesis of1-[2-hydroxy-3-propyl-4-(4-{1-[3-(1H-tetrazol-5-yl)-phenyl]-vinyl}-benzyloxy)-phenyl]-ethanone

The title compound is prepared essentially as described for1-[4-(4-{fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanoneemploying3-{1-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-vinyl}-benzonitrileto give 72 mg, of the title compound as a tan solid 65%. ¹H NMR (CDC₁₃)δ 12.87 (s, 1H), 8.00-8.07 (m, 2H), 7.83-7.86 (m, 2H), 7.65 (t, 1H),7.39-7.54 (m, 4H), 6.76 (d, 1H), 5.68 (s, 1H), 5.63 (s, 1H), 5.32 (s,2H), 2.58-2.65 (m, 5H), 1.48-1.53 (m, 2H), 0.89 (t, 3H). LCMS M−1 453.

Preparation 95 Synthesis of3-{1-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-ethyl}-benzonitrile

Add3-{1-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-vinyl}-benzonitrile(0.105 g, 0.255 mmol), ethyl acetate (50 ml) and PtO₂ (0.010 g) to aParr pressure vessel. Purge the reaction vessel with nitrogen,pressurize the reaction mixture with hydrogen (400 KPa), seal the vesseland agitate the reaction at ambient temperature. Continue the reactionfor 2.5 hours. Vent the excess hydrogen from the vessel and purge thevessel with nitrogen. Filter the reaction mixture to remove the platinumcatalyst. Add the filtrate and PtO₂ (0.019 g) to a Parr pressure vessel.Purge the reaction vessel with nitrogen, pressurize the reaction mixturewith hydrogen (400 KPa), seal the vessel and agitate the reaction atambient temperature. Continue the reaction for 6 hours. Vent the excesshydrogen from the vessel and purge the vessel with nitrogen. Filter thereaction mixture to remove the platinum catalyst and remove the solventunder vacuum. Add the concentrate, ethyl acetate (50 ml) and PtO₂ (0.022g) to a Parr pressure vessel. Purge the reaction vessel with nitrogen,pressurize the reaction mixture with hydrogen (400 KPa), seal the vesseland agitate the reaction at ambient temperature. Continue the reactionfor 18 hours. Vent the excess hydrogen from the vessel and purge thevessel with nitrogen. Filter the reaction mixture to remove the platinumcatalyst and remove the solvent under vacuum. Add the concentrate, ethylacetate (150 ml), Pt catalyst from previous filtrations and PtO₂ (0.105g) to a Parr pressure vessel. Purge the reaction vessel with nitrogen,pressurize the reaction mixture with hydrogen (400 KPa), seal the vesseland agitate the reaction at ambient temperature. Continue the reactionfor 22.5 hours. Vent the excess hydrogen from the vessel and purge thevessel with nitrogen. Filter the reaction mixture to remove the platinumcatalyst. The mixture is filtered and concentrated to give 25 mg, 25%,as a film. LCMS M−1 412.

Example 73 Synthesis of1-[2-hydroxy-3-propyl-4-(4-{1-[3-(1H-tetrazol-5-yl)-phenyl]-ethyl}-benzyloxy)-phenyl]-ethanone

The title compound is prepared essentially as described for1-[4-(4-{fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanoneemploying3-{1-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-ethyl}-benzonitrile.The title compound is obtained (12.5 mg, 45%) as a white solid. ¹H NMR(DMSO-d₆) δ 12.85 (s, 1H), 8.00 (s, 1H), 7.75-7.85 (m, 2H), 7.35-7.54(m, 6H), 6.73 (d, 1H), 5.23 (s, 2H), 4.32 (m, 1H), 2.55-2.60 (m, 5H),1.66 (d, 3H), 1.46-1.50 (m, 2H), 0.87 (t, 3H). LCMS M+1 457.

Example 74 Synthesis of1-[4-(4-{amino-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone

A mixture of1-[4-(4-{azido-[3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone(340 mg, 0.703 mmol), triphenylphosphine (195 mg, 0.74 mmol), water (0.5mL), and tetrahydrofuran (5 mL) is stirred at room temperature 48 hr.The mixture is filtered, the cake is washed with tetrahydrofuran (2 mL)and dried under vacuum to give the title compound 169 mg, 52%, as awhite solid. ¹H NMR (DMSO-d₆) δ 12.86 (s, 1H), 8.9 (bs, 2H), 8.18 (s,1H), 7.98 (d, 1H), 7.80 (d, 1H), 7.35-7.58 (m, 6H), 6.72 (d, 1H), 5.74(s, 1H), 5.28 (s, 2H), 2.58-2.62 (m, 5H), 1.46-1.54 (m, 2H), 0.88 (t,3H). LCMS M−1 456.

Example 75 Synthesis ofN-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-acetamide

A mixture of1-[4-(4-{amino-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone(80 mg, 0.175 mmol), acetyl chloride (15 μL, 0.211 mmol) anddichloromethane (1.5 mL) is stirred at room temperature. Pyridine (50μL, 0.62 mmol) is added and the mixture is stirred at room temperature24 hr. An additional portion of acetyl chloride (20 μL, 0.28 mmol) isadded and the reaction is stirred an additional 24 hr. The reactionmixture is purified as is via reversed phase C18 preparativechromatography eluting with 4:6 acetonitrile:water (0.1% trifluoroaceticacid) to 8:2 acetonitrile:water (0.1% trifluoroacetic acid) to give thetitle compound (53 mg, 61%), as a white solid. ¹H NMR (DMSO-d₆) δ 12.85(s, 1H), 8.92 (d, 1H), 8.03 (s, 1H), 7.92 (d, 1H), 7.80 (d, 1H),7.36-7.61 (m, 6H), 6.73 (d, 1H), 6.23 (d, 1H), 5.25 (s, 2H), 2.59-2.62(m, 5H), 1.97 (s, 3H), 1.46-1.53 (m, 2H), 0.88 (t, 3H). LCMS M−1=498.

Example 76 Synthesis ofN-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-methanesulfonamide

The title compound is prepared essentially as described in Example 74employing methane sulfonyl chloride and1-[4-(4-{amino-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanoneto give 22 mg, 28%, as a white solid. ¹H NMR (DMSO-d₆) δ 12.86 (s, 1H),8.49 (d, 1H), 8.17 (s, 1H), 7.91-7.94 (m, 1H), 7.80 (d, 1H), 7.60-7.62(m, 2H), 7.44-7.51 (m, 4H), 6.72 (d, 1H), 5.81 (d, 1H), 5.25 (s, 2H),2.75 (s, 3H), 2.57-2.62 (m, 5H), 1.46-1.53 (m, 2H), 0.87 (t, 3H). LCMSM+1 536.

Preparation 96 Synthesis of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-azido-methyl}-benzonitrile

A mixture of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile(3 g, 7.22 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (2.3 mL, 15.2mmol), diphenylphosphoryl azide (3.3 mL, 15.2 mmol) and tetrahydrofuran(20 mL) is stirred at 50° C. 2 hr. The mixture is concentrated and thecrude residue is purified via silica chromatography eluting with hexanesto 7:3 hexanes:ethyl acetate to give the title compound 1.77 g, 56% as awhite solid. LCMS M−1 439.

Preparation 97 Synthesis of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-amino-methyl}-benzonitrile

A mixture of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-azido-methyl}-benzonitrile(1.77 g, 4.02 mmol), triphenylphosphine (1.16 g, 4.42 mmol), water (0.5mL) and tetrahydrofuran (25 mL) is stirred 18 hr. The mixture isconcentrated, diluted with water (100 mL) and extracted to ethyl acetate(3×50 mL). The combined extracts are dried over sodium sulfate,filtered, and concentrated to a bright yellow residue. The compound isused without further purification. LCMS M−1 413.

Example 77 Synthesis of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-amino-methyl}-benzoicacid

A solution of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-amino-methyl}-benzonitrileaqueous 5N sodium hydroxide (15 mL, 75 mmol), and ethanol (50 mL) isstirred at reflux 3 hr. The pH is adjusted to 2 with concentratedaqueous hydrochloric acid and extracted with ethyl acetate (3×50 mL).The combined extracts are washed with water (50 mL) and brine (50 mL),dried over magnesium sulfate, filtered, and concentrated. The residue ispurified in 4 runs via reversed phase C18 preparatory chromatographyeluting with 8:2 water (0.1% trifluoroacetic acid):acetonitrile toacetonitrile to give 1.5 g, 87% as a white crystalline solid. ¹H NMR(DMSO-d₆) δ 13.25 (bs, 1H), 12.86 (s, 1H), 9.00 (bs, 2H), 8.14 (s, 1H),7.97 (d, 1H), 7.82 (d, 1H), 7.72 (d, 1H), 7.51-7.62 (m, 5H), 6.73 (d,1H), 5.83 (s, 1H), 5.28 (s, 2H), 2.57-2.62 (m, 5H), 1.46-1.53 (m, 2H),0.88 (t, 3H). LCMS M−1 432.

Example 78 Synthesis of3-{acetylamino-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-methyl}-benzoicacid

The title compound is prepared in a similar manner toN-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-acetamideemploying3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-amino-methyl}-benzoicacid to give a white solid (48%). ¹H NMR (DMSO-d₆) δ 13.01 (bs, 1H),12.86 (s, 1H), 8.89 (d, 1H), 7.80-7.88 (m, 3H), 7.37-7.57 (m, 6H), 6.72(d, 1H), 6.20 (d, 1H), 5.25 (s, 2H), 2.57-2.62 (m, 5H), 1.95 (s, 3H),1.46-1.53 (m, 2H), 0.88 (t, 3H). LCMS M+1 476.

General Method 1 General Procedure for the Chromatographic Separation ofa Racemic Mixture into Individual Enantiomers

The appropriate racemic compound such as1-[2-hydroxy-4-(4-{hydroxy-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-3-methyl-phenyl]-propan-1-one(56 mg, 0.126 mmol) is dissolved in a solution of acetone,tetrahydrofuran, and isopropyl alcohol. The solution is concentrated toan oil and diluted with isopropyl alcohol (1 mL). The solution isseparated via chiral chromatography in two injections utilizing aChiralcel OD, 2×25 cm column eluting isochratically with 3:1heptane:isopropyl alcohol at a flow rate of 14 mL/min, to afford 27 mgof the first eluting fraction, designated isomer 1 (Example 79, 100% ee)and 25 mg of the second eluting fraction, designated isomer 2 (Example80, 95% ee).

The following examples are prepared essentially as described in GeneralMethod 1. In Examples 83 and 84, the stereochemistry provided is acorrection of the priority document representation.

Example No. Chemical Name Structure Physical Data 791-[2-Hydroxy-4-(4-{hydroxy-[3- (1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-3-methyl- phenyl]-propan-1-one isomer 1

100% e.e. ES MS 443 M − 1. 80 1-[2-Hydroxy-4-(4-{hydroxy-[3-(1H-tetrazol-5-yl)-phenyl]- methyl}-benzyloxy)-3-methyl-phenyl]-propan-1-one isomer 2

95% e.e. ES MS 443 M − 1. 81 1-[4-(4-{Fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}- benzyloxy)-2-hydroxy-3-propyl- phenyl]-ethanoneisomer 1

100% e.e. ES MS 459 M − 1. 82 1-[4-(4-{Fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}- benzyloxy)-2-hydroxy-3-propyl- phenyl]-ethanoneisomer 2

95.5% e.e. ES MS 459 M − 1. 83 (+)-3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)- phenyl]-hydroxy-methyl}- benzoic acid isomer 1

100% e.e. ES MS 433 M − 1. [α]_(D) ²⁰ = +12.6° (C = 1.0, DMSO) 84(−)-3-{[4-(4-Acetyl-3-hydroxy-2- propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoic acid isomer 2

100% e.e. ES MS (m/z) (m ± 1) 433. [α]_(D) ²⁰ = −11.4° (C = 1.0, DMSO)

Example 85 Synthesis of sodium3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoate

Compound3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoicacid (357 mg, 0.822 mmol) is stirred in a solution of ethyl acetate (4mL) and tetrahydrofuran (4 mL) at room temperature. A solution of sodium2-ethylhexanoate (150 mg, 0.904 mmol) in ethyl acetate (2 mL) is addedand the reaction is stirred overnight. The reaction is concentrated andthe resulting thick oil is diluted with ether (5 mL) and stirredvigorously. The resulting white precipitate is filtered, and dried undervacuum to give the title compound as a white solid (94%). ¹H NMR(DMSO-d₆) δ 12.85 (s, 1H), 7.86 (s, 1H), 7.81 (d, 1H), 7.69 (d, 1H),7.38-7.39 (m, 4H), 7.33 (d, 1H), 7.19 (t, 1H), 6.72 (d, 1H), 5.84 (d,1H), 5.70 (d, 1H), 5.22 (s, 2H), 2.57-2.62 (m, 5H), 1.46-1.53 (m, 2H),0.88 (t, 3H). LCMS M−1 433 (parent acid).

Preparation 98 Synthesis of 1-(2,6-dihydroxy-biphenyl-3-yl)-ethanone

To a solution of 1-(2,4-dihydroxy-3-iodo-phenyl)-ethanone (1.0 g, 3.59mmol; 581938, may be prepared as described in G. Batu and R. Stevenson,J. Org. Chem. 1979, 44, 3948) in tetrahydrofuran/water (15 mL/3 mL) atroom temperature is added phenyl boronic acid (0.877 g, 7.19 mmol),Pd(dppf)₂Cl₂ (0.088 g, 0.107 mmol), and cesium hydroxide monohydrate(1.81 g, 10.8 mmol). After stirring for 15 hours, the mixture isfiltered through a pad of Celite®, washing with ethyl acetate. Theresidue is diluted with 30 mL of 1N hydrochloric acid and extracted withethyl acetate. The combined organic phases are washed with brine; driedover magnesium sulfate; filtered and concentrated under reducedpressure. The resulting residue is purified by flash chromatography,eluting with 30% ethyl acetate/hexanes to give the title compound as acolorless solid: MS (m/z) 228(M+); ¹H NMR (DMSO-d₆) δ 13.1 (s, 1H), 10.6(bs, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.41-7.28 (m, 5H), 6.61 (d, J=8.8 Hz,1H), 2.58 (s, 3H); R_(f)=0.58 in 40% ethyl acetate/hexanes.

The following compounds are prepared essentially as described inPreparation 98.

Prep. No. Chemical name Structure Physical data 991-(2,4-Dihydroxy-3-thiophen- 3-yl-phenyl)-ethanone

MS (m/e): 235 (M + 1) 100 1-(2,4-Dihydroxy-3-thiophen-2-yl-phenyl)-ethanone

MS (m/e): 235 (M + 1) 101 1-(4′-Fluoro-2,6-dihydroxy-biphenyl-3-yl)-ethanone

MS (m/e): 247 (M + 1) 102 1-(2,4-Dihydroxy-3-pyridin-2-yl-phenyl)-ethanone

MS (m/e): 230 (M + 1)

Preparation 103 Synthesis of3-[[4-(5-acetyl-6-hydroxy-biphenyl-2-yloxymethyl)-phenyl]-(hydroxy-methyl]-benzonitrile

To a solution of 1-(2,6-dihydroxy-biphenyl-3-yl)-ethanone (446 mg, 1.95mmol) and3-[(4-iodomethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(848 mg, 1.95 mmol) in acetone (50 mL) is added potassium carbonate (450mg, 3.25 mmol). The suspension is heated at 50° C. for 14 hours. Aftercooling to room temperature, the mixture is poured onto saturatedammonium chloride (15 mL) and extracted with ethyl acetate (4×20 mL).The combined organic extracts are combined; washed with brine; driedover magnesium sulfate; filtered and concentrated under reduced pressureto a light-yellow oil: MS (m/z): 523(M+). The residue is then dissolvedin methanol and p-toluenesulfonic acid monohydrate is added. After 1hour, the solvent is removed under reduced pressure. The resultingresidue is purified by flash chromatography (20% to 45% ethylacetate/hexanes) to give the title compound as a foam: MS (m/z):449(M+), 432(M—OH).

Preparation 104 Synthesis of3-[4-(5-acetyl-6-hydroxy-biphenyl-2-yloxymethyl)-benzoyl]-benzonitrile

To a solution of3-[[4-(5-acetyl-6-hydroxy-biphenyl-2-yloxymethyl)-phenyl]-(hydroxy-methyl]-benzonitrile(100 mg, 0.22 mmol) in dichloromethane (10 mL) is added Dess-Martinperiodinane (113.5 mg, 0.266 mmol) and potassium carbonate (33.8 mg).After five minutes, the mixture is directly loaded onto a silicacartridge. Purification by flash chromatography (linear gradient fromhexanes to 50% ethyl acetate/hexanes) gives the title compound as awhite solid (98% yield): ¹H NMR (CDC₁₃) δ 12.8 (2, 1H), 8.02-7.98 (m,2H), 7.87-7.84 (m, 1H), 7.76-7.70 (m, 3H), 7.64-7.60 (m, 1H), 7.48-7.33(m, 7H), 6.58 (d, J=8.8 Hz, 1H), 5.22 (s, 2H), 2.59 (2, 3H); R_(f)=0.29in 40% ethyl acetate/hexanes.

Preparation 105 Synthesis of1-(2-hydroxy-6-{4-[3-(2H-tetrazol-5-yl)-benzoyl]-benzyloxy}-biphenyl-3-yl)-ethanone

To a −10° C. solution of3-[[4-(5-acetyl-6-hydroxy-biphenyl-2-yloxymethyl)-phenyl]-(hydroxymethyl]-benzonitrile(100 mg, 0.22 mmol) in dichloromethane (10 mL) is added triethylsilane(2.0 equiv.) and BF₃.Et₂O (2.0 equiv). After 30 minutes, an additional 2equivalents of each reagent is added. The reaction is complete within 1hour. The mixture is quenched with 3 mL of 1N NaOH and extracted withethyl acetate. The combined organic extracts are washed with brine;dried over magnesium sulfate; filtered, and concentrated to dryness. Theresulting residue is purified by flash chromatography (15% to 35% ethylacetate/hexanes) to give the title compound as a colorless solid: ¹H NMR(CDC₁₃) δ 12.8 (2, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.50-7.32 (m, 8H),7.19-7.08 (m, 4H), 6.58 (d, J=9.2 Hz, 1H), 5.12 (s, 2H), 3.97 (s, 2H),2.59 (s, 3H).

Example 88 Synthesis of1-(2-hydroxy-6-{4-[3-(2H-tetrazol-5-yl)-benzoyl]-benzyloxy}-biphenyl-3-yl)-ethanone

The title compound is prepared essentially as described for Example 86using3-[4-(5-Acetyl-6-hydroxy-biphenyl-2-yloxymethyl)-benzoyl]-benzonitrile:MS (m/z): 489(M−1); ¹H NMR (DMSO-d₆) δ 12.8 (s, 1H), 8.34-8.30 (m, 2H),7.97 (d, J=8.8 Hz, 1H), 7.88-7.73 (m, 4H), 7.46-7.27 (m, 7H), 6.83 (d,J=8.8 Hz, 1H), 5.35 (s, 2H), 2.61 (s, 3H).

Example 89 Synthesis of1-(2-hydroxy-6-{4-[3-(2H-tetrazol-5-yl)-benzyl]-benzyloxy}-biphenyl-3-yl)-ethanone

The title compound may be prepared essentially as described for Example61 using1-(2-hydroxy-6-{4-[3-(2H-tetrazol-5-yl)-benzoyl]-benzyloxy}-biphenyl-3-yl)-ethanoneof preparation 187: MS (m/z): 475(M−1).

Example 90 Synthesis of1-(4′-fluoro-2-hydroxy-6-{4-[3-(2H-tetrazol-5-yl)-benzyl]-benzyloxy}-biphenyl-3-yl)-ethanoneExample 86 Synthesis of1-[2-hydroxy-6-(4-{hydroxy-[3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-biphenyl-3-yl]-ethanone

To a solution of3-[[4-(5-acetyl-6-hydroxy-biphenyl-2-yloxymethyl)-phenyl]-(hydroxymethyl]-benzonitrile185 (230 mg, 0.430 mmol) in iso-propanol/water (9 mL, 2/1) is addedsodium azide (4.0 equiv.) and zinc bromide (2.0 equiv.). The solution isthen heated at 110° C. for 2.5 days. After cooling to room temperature,5 mL of 1N hydrochloric acid is added and the mixture is extracted withethyl acetate (5×20 mL). The combined organic extracts are combined,washed with brine; dried over magnesium sulfate; filtered, andconcentrated under reduced pressure to dryness. The resulting residue ispurified by flash chromatography (linear gradient from dichloromethaneto 9/1/0/0.2 dichloromethane/ACN/AcOH) to give the title compound as awhite residue: MS (m/z): 492(M+); ¹H NMR (acetone-d₆) δ 12.9 (s, 1H),8.21 (s, 1H), 8.00-7.96 (m, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.62-7.50 (m,5H), 7.29-7.25 (m, 4H), 6.79 (d, J=8.8 Hz, 1H), 5.93 (s, 1H), 5.18 (s,2H), 2.60 (s, 3H).

Example 87 Synthesis of1-[4′-fluoro-2-hydroxy-6-(4-{hydroxy-[3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-biphenyl-3-yl]-ethanone

The title compound is prepared essentially as described above forExample 86 using the corresponding benzonitrile: MS (m/z): 509(M−1); ¹HNMR (DMSO-d₆) δ 12.8 (bs, 1H), 8.07 (s, 1H), 7.93 (d, J=8.8 Hz, 1H),7.85-7.82 (m, 1H), 7.53-7.15 (m, 10H), 6.79 (d, J=9.6 Hz, 1H), 6.07 (bs,1H), 5.77 (s, 1H), 5.16 (s, 2H), 2.59 (s, 3H).

The title compound may be prepared essentially as described above forExample 61 using the corresponding hydroxyl compound of Example 87: MS(m/z): 495(M+1); ¹H NMR (DMSO-d₆) δ 12.8 (s, 1H), 7.93 (d, J=8.8 Hz,1H), 7.90-7.81 (m, 2H), 7.51-7.41 (m, 2H), 7.35-7.29 (m, 2H), 7.24-7.14(m, 6H0, 6.80 (d, J=9.6 Hz, 1H), 5.33 (s, 2H), 4.00 (s, 1H), 2.58 (s,3H).

Example 91 Synthesis of3-{3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one

Add hydroxylamine (50% solution in water, 0.128 mL, 2.09 mmol) to asolution of3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(950 mg, 1.90 mmol) in ethanol (20 mL) and stir. Heat the solution toreflux for 3 hours. Cool the reaction to ambient temperature andconcentrate to dryness. Dissolve the resulting residue intetrahydrofuran (20 mL) and cool to 0° C. Add pyridine (226 mg, 2.85mmol) and 2-ethylhexyl chloroformate (403 mg, 2.09 mmol) and stir. After30 minutes, add water (50 mL) and extract with ethyl acetate. Combinethe organic extracts, dry with sodium sulfate, filter and concentrate todryness. Dissolve the resulting residue in xylenes (20 mL) and heat to130° C. After 4 hours, cool to ambient temperature and concentrate underreduced pressure to dryness. Purify the resulting residue by flashchromatography eluting with acetone:acetic acid:hexanes (25%:1%:74%) togive a white solid. Dissolve the solid in a solution of 1% aqueoushydrochloric acid:methanol, and stir. After 1 hour, concentrate underreduced pressure to dryness. Purify the resulting residue by reversephase chromatography eluting with methanol:acetic acid:water to yieldthe title compound as a white solid (22 mg, 2.4%): ¹H NMR (DMSO-d₆) δ0.86 (t, 3H), 1.48 (sextet, 2H), 2.56 (m, 5H), 5.21 (s, 2H), 5.79 (d,1H), 6.11 (d, 1H), 6.70 (d, 1H), 7.41 (m, 4H), 7.49 (t, 1H), 7.63 (m,2H), 7.79 (d, 1H), 7.89 (s, 1H), 12.83 (s, 1H), 12.96 (bs, 1H); MS (esinegative) m/z (rel intensity) 473 (100).

Preparation 106 Synthesis of1-[4-(4-bromomethyl-benzyloxy)-3-chloro-2-hydroxy-phenyl]-ethanone

Combine 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (6.00 g, 32.2 mmol)and 1,4-bis-bromomethyl-benzene (8.48 g, 31.2 mmol) and potassiumcarbonate (4.44 g, 32.2 mmol) in acetone (400 ml) and heat to reflux.After 1 h, cool to room temperature and add 10% hydrochloric acid (300mL). Filter to collect and triturate resultant solid in 1:1ether/hexanes. Purify by column chromatography, eluting with 40%tetrahydrofuran/hexanes to obtain1-[4-(4-bromomethyl-benzyloxy)-3-chloro-2-hydroxy-phenyl]-ethanone (3.00g, 8.12 mmol) as a white solid. MS (m/z): 368.9 (M−1).

Preparation 107 Synthesis of1-(3-bromo-phenyl)-3-dimethylamino-propenone

Combine 1-(3-bromo-phenyl)-ethanone (10 g, 50.2 mmol) anddimethylformamide dimethylacetal (60 g, 502 mmol) in a sealed tube, heatto 150° C. for 12 hours. Cool the solution and evaporate the excessdimethylformamide dimethylacetal. Purify residue by columnchromatography to obtain the title compound (3.05 g, 12.0 mmol) as awhite solid. MS (m/z): 254.1 (M).

Preparation 108 Synthesis of 4-(3-bromo-phenyl)-pyrimidin-2-ol

Combine 1-(3-bromo-phenyl)-3-dimethylamino-propenone (3.00 g, 11.8mmol), urea (544 mg, 11.8 mmol), sodium ethoxide (4.00 g, 21% wt inethanol) and ethanol (24 mL) and heat to 150° C. in sealed tubeovernight. Cool to room temperature and pour into 1% hydrochloric acid(50 mL). Collect white solid by filtration to obtain4-(3-bromo-phenyl)-pyrimidin-2-ol (2.60 g, 10.4 mmol). MS (m/z): 251.2(M+1).

Preparation 109 Synthesis of4-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-pyrimidin-2-ol

Combine 4-(3-bromo-phenyl)-pyrimidin-2-ol (1.50 g, 5.97 mmol),bis(neopentyl glycolato)diboron (1.62 g, 7.17 mmol), Pd(dppf)Cl₂ (505mg, 0.597 mmol) and potassium acetate (1.76 g, 17.9 mmol) in a purged(N₂) flask, add dry DMSO (50 mL) and plunge into a 80° C. bath. Heatovernight, then pour into 1% hydrochloric acid (100 mL). Neutralize withsodium bicarbonate, and extract with ethyl acetate, dry, filter andcondense to afford4-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-pyrimidin-2-ol (300mg) as a brown solid. MS (m/z): 173.1 (M−C5H₁₀BO₂+1).

Example 92 Synthesis of1-(3-chloro-2-hydroxy-4-{4-[3-(2-hydroxy-pyrimidin-4-yl)-benzyl]-benzyloxy}-phenyl)-ethanone

Prepare a solution of1-[4-(4-bromomethyl-benzyloxy)-3-chloro-2-hydroxy-phenyl]-ethanone (402mg, 1.06 mmol) and boronic ester (300 mg, 1.05 mmol) in aqueous sodiumcarbonate (2 M, 3 mL) and DME (10 ml). Treat withtetrakis(triphenylphosphine)palladium(0) (61 mg, 0.05 mmol) and degasfive times (house vacuum/nitrogen). Heat the light yellow partition to70° C., at which time it turns from yellow to black. Cool the mixture tort, then dilute with water and ethyl acetate. Separate the layers andextract the aqueous layer with ethyl acetate. Combine the organic layersand wash with brine, dry (MgSO₄), filter, and concentrate in vacuo toafford a solid residue. Purify the residue by reverse phase HPLC (C-18column) eluting with a 15 to 85% acetonitrile/water gradient to afford1-(3-chloro-2-hydroxy-4-{4-[3-(2-hydroxy-pyrimidin-4-yl)-benzyl]-benzyloxy}-phenyl)-ethanone(5 mg, 0.01 mmol) as a white solid: ¹H NMR (DMSO-d₆) δ 2.60 (s, 3H),5.10 (s, 2H), 5.34 (s, 2H), 6.86 (d, 1H), 7.12 (d, 1H), 7.40 (d, 2H),7.46 (d, 2H), 7.55 (m, 3H), 7.92 (d, 1H), 8.12 (d, 2H), 8.45 (d, 1H),13.12 (s, 1H); MS (m/z): 459.1 (M−1).

Preparation 110 Synthesis of 4-(3-bromo-phenyl)-pyrimidin-2-ylamine

Combine 1-(3-bromo-phenyl)-3-dimethylamino-propenone (3.00 g, 11.8 mmol)and guanidinium chloride (1.12 g, 11.8 mmol), sodium ethoxide (5 mL, 21%wt solution in ethanol), absolute EtOH (24 mL) and heat to refluxovernight. Cool to room temperature and pour into 1% hydrochloric acid(200 mL). Extract with ethyl acetate, dry over sodium sulfate andcondense to afford 4-(3-bromo-phenyl)-pyrimidin-2-ylamine (930 mg, 3.72mmol) as a white solid. MS (m/z): 250.2 (M).

Preparation 111 Synthesis of4-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-pyrimidin-2-ylamine

The title compound is prepared essentially as described for Preparation109 using 4-(3-bromo-phenyl)-pyrimidin-2-ylamine (2.00 g, 8.00 mmol).The title compound is isolated (1.71 g, 6.04 mmol) as a brown solid. MS(m/z): 216.2 (M−C5H₈+1).

Example 93 Synthesis of1-(4-{4-[3-(2-amino-pyrimidin-4-yl)-benzyl]-benzyloxy}-3-chloro-2-hydroxy-phenyl)-ethanone

The title compound is prepared essentially as described in Example 92using4-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-pyrimidin-2-ylamine(327 mg, 1.15 mmol) and1-[4-(4-bromomethyl-benzyloxy)-3-chloro-2-hydroxy-phenyl]-ethanone (400mg, 1.08 mmol). The title compound is isolated (109 mg, 0.237 mmol) as ayellow solid: ¹H NMR (DMSO-d₆) δ 2.10 (s, 3H), 4.04 (s, 2H), 5.30 (s,2H), 6.62 (m, 2H), 6.88 (d, 1H), 7.08 (m, 1H), 7.29 (m, 2H), 7.40 (m,4H), 7.92 (m, 3H), 8.28 (d, 1H), 13.12 (s, 1H); MS (m/z): 458.2 (M−1).

Preparation 112 Synthesis of3-[[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

Add diisopropylazodicarboxylate (DIAD, 5.418 g, 26.80 mmol) to asolution of 1-(3-chloro-2,4-dihydroxy-phenyl)ethanone (5.000 g, 26.80mmol),3-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(8.666 g, 26.80 mmol), and triphenylphosphine (7.028 g, 26.80 mmol) intetrahydrofuran (0.200M) at 0° C. Stir for 2 hours while warming to roomtemperature. Add silica gel and evaporate solvent. Chromatograph withBiotage Flash 75, eluting with 50-90% ethyl acetate/hexanes to affordthe title compound as a white solid (13.00 g, 26.42 mmol, 98%): MS(m/z): 490 (M−H).

Preparation 113 Synthesis of3-[[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoicacid

Heat a solution of3-[[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(10.00 g, 20.33 mmol) and potassium hydroxide (22.81 g, 406.5 mmol) inethanol (100 mL) and water (25 mL) at reflux for 3 days. Evaporatevolatiles and acidify with 1N hydrochloric acid and extract with CH₂Cl₂(3×). Combine organic layers, dry (sodium sulfatesodium sulfate) andevaporate to afford the title compound as a white solid (10.00 g, 19.57mmol, 96%): MS (m/z): 510 (M−H).

Example 94 Synthesis of3-{[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoicacid

Add p-toluenesulfonic acid (16.8 mg, 0.098 mmol) to a solution of3-[[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoicacid (1.00 g, 1.96 mmol) in methanol (0.20M) and stir overnight.Evaporate solvents, dilute with ethyl acetate and wash with water (1×)and brine (1×). Dry and concentrate to afford the title compound as awhite solid (0.786 mg, 1.84 mmol, 94%): MS (m/z): 426 (M−H).

Preparation 114 Synthesis of1-(3-{[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-hydroxy-methyl}-phenyl)-2-chloro-ethanone

Add oxalyl chloride (256 mg, 2.02 mmol) to a solution of3-{[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoicacid (0.786 mg, 1.84 mmol) in tetrahydrofuran (0.20M). Adddimethylformamide (5 drops). Add ethereal solution of diazomethane (1.90mmol) and stir for 2 hours. Add hydrochloric acid (4N in dioxane) toquench unreacted diazomethane and evaporate solvents to afford the titlecompound (0.786 mg, 1.84 mmol, 94%): MS (m/z): 457 (M−H).

Example 95 Synthesis of4-(3-{[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-hydroxy-methyl}-phenyl)-3H-thiazol-2-one

Heat a solution of1-(3-{[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-hydroxy-methyl}-phenyl)-2-chloro-ethanone(0.075 mg, 0.163 mmol) and potassium thiocyanate (159 mg, 1.63 mmol) inethanol (0.20M) overnight at 70° C. Evaporate solvents and chromatographresidue. Major fraction isolated was the title compound (0.005 g, 0.010mmol, 6.1%): ¹H NMR (400 MHz, DMSO-d₆) δ 2.61 (s, 3H), 5.10 (s, 2H),5.30 (s, 2H), 5.82 (s, 1H), 6.11 (s, 1H), 6.88 (d, J=9.8 Hz, 1H), 7.41(m, 4H), 7.49 (m, 1H), 7.71 (d, J=7.4 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H),7.92 (d, J=9.4 Hz, 1H), 8.04 (s, 1H), 13.12 (s, 1H). MS (m/z): 480(M−H).

Preparation 115 Synthesis of3-[[4-(3-hydroxy-2-methyl-4-propionyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

The title compound is prepared essentially as described in Preparation112 employing 1-(2,4-dihydroxy-3-methyl-phenyl)-propan-1-one (5.00 g,27.7 mmol). The title compound is isolated as a white powder (10.0 g,20.5 mmol, 74%). MS (m/z): 484 (M−H).

Preparation 116 Synthesis of3-[[4-(3-hydroxy-2-methyl-4-propionyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoicacid

The title compound is prepared essentially as described in Preparation113 employing3-[[4-(3-hydroxy-2-methyl-4-propionyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(5.00 g, 10.3 mmol) and potassium hydroxide (11.6 g, 206 mmol) inethanol (100 mL) and water (25 mL) at reflux for 3 days. Concentrate thereaction mixture and acidify with 1N hydrochloric acid, then extractwith dichloromethane (3×). Combine organic layers, dry (sodiumsulfatesodium sulfate) and evaporate to afford the title compound as awhite solid (2.11 g, 4.18 mmol, 40%): MS (m/z): 503 (M−H).

Preparation 117 Synthesis of1-(4-{4-[[3-(2-chloro-acetyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-2-hydroxy-3-methyl-phenyl)-propan-1-one

Add oxalyl chloride (0.660 mg, 5.20 mmol) to a solution of3-[[4-(3-hydroxy-2-methyl-4-propionyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoicacid (2.50 g, 5.00 mmol) in tetrahydrofuran (0.20M). Adddimethylformamide (5 drops). Add ethereal solution of diazomethane (15.0mmol) and stir for 2 hours. Add hydrochloric acid (4N in dioxane) toquench unreacted diazomethane and evaporate solvents to afford the titlecompound (2.25 g, 4.19 mmol, 85%): MS (m/z): 536 (M−H).

Example 96 Synthesis of4-(3-{hydroxy-[4-(3-hydroxy-2-methyl-4-propionyl-phenoxymethyl)-phenyl]-methyl}-phenyl)-3H-thiazol-2-one

Heat a solution of1-(4-{4-[[3-(2-chloro-acetyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-2-hydroxy-3-methyl-phenyl)-propan-1-one(0.250 mg, 0.466 mmol) and potassium thiocyanate (90.5 mg, 0.931 mmol)in ethanol (0.20 M) overnight at 70° C. Add p-toluenesulfonic acid (10mg) and stir overnight. Evaporate solvents and chromatograph residue.Major fraction isolated was the title compound (0.086 g, 0.179 mmol,39%): ¹H NMR (400 MHz, DMSO-d₆) δ 1.09 (t, J=7.2 Hz, 3H), 2.02 (s, 3H),3.03 (q, J=9.6 Hz, 2H), 5.10 (s, 2H), 5.20 (s, 2H), 5.82 (d, J=3.9 Hz,1H), 6.11 (d, J=3.9 Hz, 1H), 6.70 (d, J=9.0 Hz, 1H), 7.42 (q, J=11.2 Hz,4H), 7.51 (t, J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.81 (d, J=9.0 Hz,1H), 7.87 (d, J=8.2 Hz, 1H), 8.04 (s, 1H), 12.88 (s, 1H). MS (m/z): 474(M−H).

Example 97 Synthesis of1-[4-(4-{[3-(2-amino-thiazol-4-yl)-phenyl]-hydroxy-methyl}-benzyloxy)-2-hydroxy-3-methyl-phenyl]-propan-1-one

Heat a solution of1-(4-{4-[[3-(2-chloro-acetyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-2-hydroxy-3-methyl-phenyl)-propan-1-one(0.250 mg, 0.466 mmol) and thiourea (71 mg, 0.931 mmol) in ethanol (0.20M) overnight at 70° C. Add p-toluenesulfonic acid (10 mg) and stirovernight. Evaporate solvents and chromatograph residue. Major fractionisolated was the title compound (0.115 g, 0.243 mmol, 52%): ¹H NMR (400MHz, DMSO-d₆) δ 1.09 (t, J=10.5 Hz, 3H), 2.02 (s, 3H), 3.03 (q, J=14.4Hz, 2H), 5.20 (s, 2H), 5.75 (s, 1H), 6.70 (d, J=9.0 Hz, 1H), 7.14 (s,1H), 7.37 (d, J=6.43 Hz, 1H), 7.42 (m, 6H), 7.60 (m, 1H), 7.80 (m, 2H),12.89 (s, 1H). MS (m/z): 473 (M−H).

Preparation 118 Synthesis of3-[[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

The title compound is prepared essentially as described in Preparation112 employing 1-(2,4-dihydroxy-3-methyl-phenyl)-ethanone (5.00 g, 30.1mmol). The title compound is isolated as a white powder (3.20 g, 6.79mmol, 23%). MS (m/z): 470 (M−H).

Preparation 119 Synthesis of3-[[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoicacid

The title compound is prepared essentially as described in Preparation113 employing3-[[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(3.20 g, 6.79 mmol) and potassium hydroxide (7.62 g, 136 mmol) inethanol (100 mL) and water (25 mL) at reflux for 3 days. Evaporatevolatiles and acidify with 1N hydrochloric acid and extract with threeportions of methylene chloride. Combine organic layers, dry (sodiumsulfate) and evaporate to afford the title compound as a white solid(1.10 g, 2.24 mmol, 33%): MS (m/z): 490 (M−H).

Preparation 120 Synthesis of3-[[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoicacid thiosemicarbazide

Add oxalyl chloride (0.660 mg, 5.20 mmol) to a solution of3-[[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoicacid, 1.00 g, 2.04 mmol) in tetrahydrofuran (0.20M). Adddimethylformamide (5 drops). Add pyridine (0.322 g, 4.08 mmol) andthiosemicarbazide (0.223 g, 2.45 mmol). Stir the reaction overnight.Evaporate solvents. Dissolve brown tar in acetone/water. Extract withCH₂Cl₂ (3×) and ethyl acetate (3×). Combine organic extracts, dry andconcentrate to afford the title compound, which was used without furtherpurification (1.20 g, 2.04 mmol, 99%): MS (m/z): 563 (M−H).

Preparation 121 Synthesis of1-(2-hydroxy-4-{4-[[3-(5-mercapto-4H-[1,2,4]triazol-3-yl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-3-methyl-phenyl)-ethanone

Heat a solution of3-[[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoicacid thiosemicarbazide (1.20 g, 2.04 mmol) and potassium hydroxide(0.228 g, 4.08 mmol) in acetone (5.0 mL) and water (5.0 mL) overnight.Acidify with 2N hydrochloric acid and extract with ethyl acetate (5×).Combine organic layers and wash with brine, dry, and concentrate toafford the title compound which was used without further purification(1.12 g, 2.04 mmol, 99%). MS (m/z): 544 (M−H).

Example 98 Synthesis of1-[2-hydroxy-4-(4-{hydroxy-[3-(5-mercapto-4H-[1,2,4]triazol-3-yl)-phenyl]-methyl}-benzyloxy)-3-methyl-phenyl]-ethanone

Stir a solution of1-(2-hydroxy-4-{4-[[3-(5-mercapto-4H-[1,2,4]triazol-3-yl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-3-methyl-phenyl)-ethanone(1.12 g, 2.04 mmol) and p-toluenesulfonic acid (50 mg) in methanol(0.2M). Dilute with ethyl acetate and wash with water. Dry the organiclayer and concentrate to afford the title compound (0.250 g, 0.551 mmol,27% overall from acid chloride). ¹H NMR (400 MHz, DMSO-d₆) δ 2.02 (s,3H), 2.50 (s, 3H), 5.21 (s, 2H), 5.76 (s, 1H), 6.05 (s, 1H), 6.71 (d,J=9.4 Hz, 1H), 7.39 (m, 6H), 7.53 (m, 1H), 7.73 (m, 1H), 7.78 (d, J=9.0Hz, 1H), 7.98 (s, 1H), 12.83 (s, 1H). MS (m/z): 460 (M−H).

Example 99 Synthesis of3-{3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one

Add hydroxylamine (50% solution in water, 0.128 mL, 2.09 mmol) to asolution of3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile(950 mg, 1.90 mmol) in ethanol (20 mL) and stir. Heat solution toreflux. After 3 hours, cool to ambient temperature and concentrate togive a residue. Dissolve the residue in tetrahydrofuran (20 mL) and coolto 0° C. Add pyridine (226 mg, 2.85 mmol) and 2-ethylhexyl chloroformate(403 mg, 2.09 mmol) and stir. After 30 minutes, add water (50 mL) andextract with ethyl acetate. Combine the organic layers, dry with sodiumsulfate filter and concentrate to give a residue. Dissolve the residuein xylenes (20 mL) and heat to 130° C. After 4 hours, cool to ambienttemperature and concentrate under reduced pressure to give a residue.Purify the residue by flash chromatography eluting with acetone:aceticacid:hexanes (25%:1%:74%) to give a white solid. Dissolve the solid in asolution of 1% aqueous hydrochloric acid:methanol, and stir. After 1hour, concentrate under reduced pressure to give a residue. Purify theresidue by reverse phase chromatography eluting with methanol:aceticacid:water to yield the title compound as a white solid (22 mg, 2.4%):¹H NMR (DMSO-d₆) δ 0.86 (t, 3H), 1.48 (sextet, 2H), 2.56 (m, 5H), 5.21(s, 2H), 5.79 (d, 1H), 6.11 (d, 1H), 6.70 (d, 1H), 7.41 (m, 4H), 7.49(t, 1H), 7.63 (m, 2H), 7.79 (d, 1H), 7.89 (s, 1H), 12.83 (s, 1H), 12.96(bs, 1H); MS (esi negative) m/z (rel intensity) 473 (100).

Preparation 122 Synthesis of3-(tetrahydro-pyran-2-yloxymethyl)-benzonitrile

Add p-toluene sulphonic acid (2.11 g, 12.2 mmol) to a solution of3-hydroxymethyl-benzonitrile (16.30 g, 122.4 mmol) and3,4-dihydro-2H-pyran (51.5 g, 612 mmol) in dichloromethane (500 ml) andstir. After 90 minutes, pour reaction into saturated sodium bicarbonate,remove organics, dry with sodium sulfate, filter and concentrate to givea dark brown oil. Purify the residue by flash chromatography elutingwith a gradient of 10-15% ethyl acetate:hexanes to yield the titleproduct as a clear oil (16.20 g, 61%): ¹H NMR (CDC₁₃) δ 1.53-1.91 (m,6H), 3.56 (m, 1H), 3.88 (m, 1H), 4.53 (d, 1H), 4.72 (t, 1H), 4.81 (d,1H), 7.45 (t, 1H), 7.58 (m, 2H), 7.69 (s, 1H).

Preparation 123 Synthesis of3-[3-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-4H-[1,2,4]oxadiazol-5-one

Add 50% aqueous hydroxylamine (9.73 g, 147 mmol) dropwise to a refluxingsolution of 3-(tetrahydro-pyran-2-yloxymethyl)-benzonitrile (8.00 g,36.8 mmol) in isopropanol (0.1M). After 2 hours, cool to roomtemperature and concentrate under reduced pressure to give a residue.Dissolve the residue in dioxane (0.1M). Add carbonyldiimidazole (7.16 g,44.2 mmol) and heat to 110° C. After 30 minutes, cool to roomtemperature and pour into water. Extract with ethyl acetate. Combine theorganic layers, dry with sodium sulfate, filter and concentrate underreduced pressure to yield the title product as a white solid (9.10 g,89%): ¹H NMR (CDC₁₃) δ 1.53-1.95 (m, 6H), 3.59 (m, 1H), 3.93 (m, 1H),4.58 (d, 1H), 4.77 (t, 1H), 4.88 (d, 1H), 7.52 (t, 1H), 7.57 (d, 1H),7.71 (d, 1H), 7.82 (s, 1H), 11.16 (bs, 1H).

Preparation 124 Synthesis of3-(3-hydroxymethyl-phenyl)-4H-[1,2,4]oxadiazol-5-one

Add 10% hydrochloric acid (100 ml) to a solution of3-[3-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-4H-[1,2,4]oxadiazol-5-one(4.50 g, 16.3 mmol) in tetrahydrofuran (0.1M) and stir. After 18 hours,pour reaction into brine and extract with ethyl acetate. Combine theorganic layers, dry with sodium sulfate, filter and concentrate underreduced pressure to yield the title product as a white solid (3.10 g,99%): ¹H NMR (DMSO-d₆) δ 4.57 (s, 2H), 7.55 (m, 2H), 7.67 (dt, 1H), 7.81(m, 1H), 12.95 (bs, 1H).

Preparation 125 Synthesis of3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzaldehyde

Add PCC (5.22 g, 24.2 mmol) to a solution of3-(3-hydroxymethyl-phenyl)-4H-[1,2,4]oxadiazol-5-one (3.10 g, 16.1 mmol)in tetrahydrofuran:dichloromethane (125 mL:125 mL) and stir. After 4hours concentrate under reduced pressure to give a residue. Purify theresidue by flash chromatography eluting with ethylacetate:hexanes:acetic acid (50%:50%:0.1%) to yield the title product asa white solid (2.20 g, 72%): ¹H NMR (DMSO-d₆) δ 7.83 (t, 1H), 8.10-8.17(m, 2H), 8.35 (m, 1H), 10.09 (s, 1H), 13.15 (bs, 1H).

Preparation 126 Synthesis of1-[2-hydroxy-4-(4-iodo-benzyloxy)-3-propyl-phenyl]-ethanone

Add 1-bromomethyl-4-iodo-benzene (10.00 g, 33.7 mmol) to a solution of1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (6.54 g, 33.7 mmol) andcesium carbonate (13.2 g, 40.4 mmol) in acetone (500 mL) and stir. After48 hours, pour the reaction into water and extract with ethyl acetate.Combine the organic layers, dry with sodium sulfate, filter andconcentrate under reduced pressure to give a residue. Purify the residueby flash chromatography eluting with a gradient of ethyl acetate:hexanesto yield the title product as a yellow solid (7.20 g, 52%): ¹H NMR(CDC₁₃) δ 0.95 (t, 3H), 1.56 (sextet, 2H), 2.56 (s, 3H), 2.69 (t, 2H),5.09 (s, 2H), 6.43 (d, 1H), 7.15 (d, 2H), 7.57 (d, 1H), 7.73 (d, 2H),12.74 (s, 1H).

Preparation 127 Synthesis of1-(4-iodo-benzyloxy)-2-propyl-3-trimethylsilanyloxy-4-(1-trimethyl-silanyloxy-vinyl)-benzene

Add lithium hexamethyldisilazide (1M solution in tetrahydrofuran, 5.36ml, 5.36 mmol) to a solution of1-[2-hydroxy-4-(4-iodo-benzyloxy)-3-propyl-phenyl]-ethanone (1.00 g,2.44 mmol) in tetrahydrofuran (25 mL) cooled to −78° C. After 1 hour,add trimethylsilyl chloride (794 mg, 7.31 mmol). After 1 hour, warmreaction to room temperature and stir overnight. Pour the reaction intosaturated sodium bicarbonate and extract with ethyl acetate. Combine theorganic layers, dry with sodium sulfate, filter, and concentrate. Dry onhigh-vac overnight to yield the title product as a dark yellow oil (1.35g, 99%): ¹H NMR (CDC₁₃) δ 0.16 (s, 9H), 0.23 (s, 9H), 0.94 (t, 3H), 1.52(sextet, 2H), 2.60 (t, 2H), 4.49 (s, 1H), 4.53 (s, 1H), 4.99 (s, 2H),6.49 (d, 1H), 7.10 (d, 1H), 7.17 (d, 2H), 7.71 (d, 2H).

Example 100 Synthesis of3-(3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-phenyl)-4H-[1,2,4]oxadiazol-5-one

Add isopropyl magnesium chloride (2M solution in tetrahydrofuran, 0.496ml, 0.992 mmol) to a solution of1-(4-iodo-benzyloxy)-2-propyl-3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-benzene(500 mg, 0.901 mmol) in tetrahydrofuran (0.1M) at 0° C. After 15minutes, warm to room temperature. After 1 hour, cool to −78° C. Addsodium hydride (60% dispersion, 24 mg, 0.992 mmol) to a solution of3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzaldehyde (189 mg, 0.992mmol) in tetrahydrofuran (0.1M). Sonicate the solution for 5 minutes,then add it via syringe to the gringard reagent. After 30 minutes warmthe reaction to room temperature. Quench with 10% aq hydrochloric acid(3 mL). Pour the reaction into brine and extract with 25% isopropylalcohol:75% dichloromethane. Combine organic layers, dry with sodiumsulfate, filter and concentrate under reduced pressure to give aresidue. Purify the residue by flash chromatography eluting with ethylacetate:hexanes:acetic acid 50%:50%:0.1% to yield the title product as aoff white solid (110 mg, 26%): ¹H NMR (DMSO-d₆) δ 0.86 (t, 3H), 1.47(sextet, 2H), 2.56 (m, 5H), 5.21 (s, 2H), 5.79 (d, 1H), 6.11 (d, 1H),6.70 (d, 1H), 7.41 (q, 4H), 7.51 (t, 1H), 7.63 (t, 2H), 7.78 (d, 1H),7.90 (s, 1H), 12.83 (s, 1H), 12.97 (bs, 1H); MS (esi negative) m/z (relintensity) 473 (100).

Preparation 128 Synthesis of1-[3-chloro-2-hydroxy-4-(4-iodo-benzyloxy)-phenyl]-ethanone

Add 1-bromomethyl-4-iodo-benzene (10.00 g, 33.7 mmol) to a solution of1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (7.92 g, 42.4 mmol) andcesium carbonate (16.6 g, 50.9 mmol) in dimethylformamide (250 mL) andstir. After 18 hours, pour reaction into water and extract with ethylacetate. Combine organic layers and wash with 2N NaOH. Dry with sodiumsulfate, filter, and concentrate under reduced pressure to give aresidue. Purify the residue by flash chromatography eluting with agradient of ethyl acetate:hexanes to yield the title product as a tansolid (4.00 g, 23%): ¹H NMR (DMSO-d₆) δ 2.62 (s, 3H), 5.33 (s, 2H), 6.87(d, 1H), 7.27 (d, 2H), 7.78 (d, 2H), 7.94 (d, 1H), 13.13 (s, 1H).

Preparation 129 Synthesis of2-chloro-1′-(4-iodo-benzyloxy)-3-trimethylsilanyloxy-4-(1′-trimethyl-silanyloxy-vinyl)-benzene

Add sodium hexamethyldisilazide (1M solution in tetrahydrofuran, 21.9mL, 21.9 mmol) to a solution of1-[3-chloro-2-hydroxy-4-(4-iodo-benzyloxy)-phenyl]-ethanone (4.00 g,9.94 mmol) in tetrahydrofuran (100 mL) chilled to −78° C. After 1 hour,add trimethylsilyl chloride (3.24 g, 29.8 mmol). After 1 hour, warmreaction to room temperature and stir overnight. Pour reaction intosaturated sodium bicarbonate and extract with ethyl acetate. Combineorganic layers, dry with sodium sulfate, filter, and concentrate. Dry invacuo overnight to yield the title product as a dark yellow oil (5.30 g,98%): ¹H NMR (CDC₁₃) δ 0.21 (s, 9H), 0.28 (s, 9H), 4.55 (s, 1H), 4.79(s, 1H), 5.08 (s, 2H), 6.56 (d, 1H), 7.22 (m, 3H), 7.71 (d, 2H).

Preparation 130 Synthesis of3-(3-{[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-hydroxy-methyl}-phenyl)-4H-[1,2,4]oxadiazol-5-one

Add isopropyl magnesium chloride (2M solution in tetrahydrofuran, 1.01ml, 2.02 mmol) to a solution of2-chloro-1-(4-iodo-benzyloxy)-3-trimethylsilanyloxy-4-(1′-trimethylsilanyloxy-vinyl)-benzene(1.00 g, 1.83 mmol) in tetrahydrofuran (0.1M) at 0° C. After 15 minutes,warm to room temperature. After 1 hour, cool to −78° C. Add sodiumhydride (60% dispersion, 80 mg, 2.01 mmol) to a solution of3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzaldehyde (348 mg, 1.83mmol) in tetrahydrofuran (0.1M). Sonicate the solution for 5 minutes,then add it via syringe to the gringard reagent. After 30 minutes, warmthe reaction to room temperature. Quench with 10% aq hydrochloric acid.Pour the reaction into brine and extract with 25% isopropyl alcohol:75%dichloromethane. Combine the organic layers, dry with sodium sulfate,filter, and concentrate under reduced pressure to give a residue. Purifythe residue by flash chromatography eluting with 5% methanol:methylenechloride to yield the title product as a off white solid (389 mg, 46%):¹H NMR (DMSO-d₆) δ 2.61 (s, 3H), 5.31 (s, 2H), 5.80 (d, 1H), 6.12 (d,1H), 6.87 (d, 1H), 7.43 (m, 4H), 7.51 (t, 1H), 7.64 (tt, 2H), 7.90 (t,1H), 7.91 (d, 1H), 12.96 (bs, 1H), 13.12 (s, 1H); MS (esi negative) m/z(rel intensity) 465 (100).

Preparation 131 Synthesis of3-(tert-butyl-dimethyl-silanyloxymethyl)-benzonitrile

Add tert-butyl-chloro-dimethyl-silane (11.9 g, 78.9 mmol) to a solutionof 3-hydroxymethyl-benzonitrile (10.00 g, 75.10 mmol) and imidazole(6.14 g, 90.1 mmol) in dichloromethane (1 L) and stir. After 18 hours,pour reaction into 1% hydrochloric acid. Remove organic layer, dry withsodium sulfate, filter, and concentrate under reduced pressure to yieldthe title product as a clear yellow oil (18.5 g, 99%): ¹H NMR (CDC₁₃) δ0.12 (s, 6H), 0.95 (s, 9H), 4.75 (s, 2H), 7.43 (t, 1H), 7.53 (d, 2H),7.63 (s, 1H).

Preparation 132 Synthesis of[3-(2-oxo-2,3-dihydro-2λ⁴-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-methanol

Add hydroxylamine (50% aqueous solution, 5.34 g, 80.8 mmol) dropwise toa refluxing solution of3-(tert-butyl-dimethyl-silanyloxymethyl)-benzonitrile (5.00 g, 20.2mmol) in isopropanol (0.1 M). After 2 hours, concentrate the reactionunder reduced pressure and azeotrope with toluene. Add dichloromethane(0.1 M) and pyridine (1.92 g, 24.3 mmol) and cool reaction to −78° C.Add thionyl chloride (2.64 g, 22.2 mmol) via syringe. After 4 hours,warm the reaction to room temperature. Concentrate the reaction underreduced pressure. Add tetrahydrofuran (0.1M) and 10% hydrochloric acid(0.1M) and stir. After 18 hours, add brine and extract with 25%isopropyl alcohol:75% dichloromethane. Combine organic layers, dry withsodium sulfate, filter and concentrate under reduced pressure to yieldthe title product as a yellow solid (3.90 g, 91%): ¹H NMR (DMSO-d₆) δ4.63 (s, 2H), 5.42 (bs, 1H), 7.59 (m, 2H), 7.75 (dt, 1H), 7.88 (s, 1H),12.23 (bs, 1H).

Preparation 133 Synthesis of3-(2-oxo-2,3-dihydro-2λ⁴-[1,2,3,5]oxathiadiazol-4-yl)-benzaldehyde

Add PCC (5.94 g, 27.6 mmol) to a solution of[3-(2-oxo-2,3-dihydro-214-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-methanol(3.90 g, 18.4 mmol) in dichloromethane (100 mL):tetrahydrofuran (100 mL)and stir. After 2 hours, concentrate the reaction under reduced pressureand purify the residue by flash chromatography eluting with 35%acetone:hexanes to yield the title product as a white solid (2.0 g,52%): ¹H NMR (DMSO-d₆) δ 7.83 (t, 1H), 8.16 (m, 2H), 8.38 (t, 1H), 10.10(s, 1H), 12.42 (bs, 1H).

Example 101 Synthesis of1-[3-chloro-2-hydroxy-4-(4-{hydroxy-[3-(2-oxo-2,3-dihydro-2λ⁴-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-methyl}-benzyloxy)-phenyl]-ethanone

Add isopropyl magnesium chloride (2 M solution in tetrahydrofuran, 1.16ml, 2.31 mmol) to a solution of2-chloro-1-(4-iodo-benzyloxy)-3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-benzene(1.15 g, 2.10 mmol) in tetrahydrofuran (0.1M) chilled to 0° C. After 15minutes warm to room temperature. After 1 hour cool the reaction to −78°C. Add sodium hydride (60% dispersion, 101 mg, 2.52 mmol) to a solutionof 3-(2-oxo-2,3-dihydro-214-[1,2,3,5]oxathiadiazol-4-yl)-benzaldehyde(442 mg, 2.10 mmol) in tetrahydrofuran (0.1M). Sonicate the solution for5 minutes, then add it via syringe to the gringard reagent. After 30minutes warm the reaction to room temperature. Quench with 10% aqhydrochloric acid. Pour the reaction into brine and extract with 25%isopropyl alcohol:75% dichloromethane. Combine the organic layers, drywith sodium sulfate, filter and concentrate under reduced pressure togive a residue. Purify the residue by flash chromatography eluting withmethanol:dichloromethane to yield the title product as a white solid(142 mg, 14%): ¹H NMR (DMSO-d₆) δ 2.61 (s, 3H), 5.31 (s, 2H), 5.81 (s,1H), 6.13 (bs, 1H), 6.88 (d, 1H), 7.43 (m, 4H), 7.51 (t, 1H), 7.60 (d,1H), 7.68 (dt, 1H), 7.92 (m, 2H), 12.19 (bs, 1H), 13.12 (s, 1H); MS (esinegative) m/z (rel intensity) 484.9 (100).

Preparation 134 Synthesis is of1-[3-chloro-2-hydroxy-4-(3-iodo-benzyloxy)-phenyl]-ethanone

Add triphenylphosphine (13.6 g, 51.7 mmol) and DIAD (10.5 g, 51.7 mmol)to a solution of (3-iodo-phenyl)-methanol (11.0 g, 47.0 mmol) and1-(3-Chloro-2,4-dihydroxy-phenyl)-ethanone (8.77 g, 47.0 mmol) indichloromethane:tetrahydrofuran (250 ml:250 ml) and stir. After 18hours, concentrate the reaction, and load directly onto silica. Purifythe residue by flash chromatography eluting with acetone:hexanes toyield the title product as a white solid (12.2 g, 64%): ¹H NMR (DMSO-d₆)δ 2.62 (s, 3H), 5.34 (s, 2H), 6.88 (d, 1H), 7.23 (t, 1H), 7.48 (d, 1H),7.72 (d, 1H), 7.87 (s, 1H), 7.96 (d, 1H), 13.14 (s, 1H).

Preparation 135 Synthesis of2-chloro-1-(3-iodo-benzyloxy)-3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-benzene

Add sodium hexamethyldisilazide (1 M solution in tetrahydrofuran, 20.2ml, 20.2 mmol) to a solution of1-[3-chloro-2-hydroxy-4-(4-iodo-benzyloxy)-phenyl]-ethanone (3.70 g,9.19 mmol) in tetrahydrofuran (100 mL) chilled to −78° C. After 1 hour,add trimethylsilyl chloride (3.00 g, 27.6 mmol). After 1 hour, warmreaction to room temperature and stir overnight. Pour reaction intosaturated sodium bicarbonate and extract with ethyl acetate. Combineorganic layers, dry with sodium sulfate, filter, and concentrate. Dry onhigh-vac overnight to yield the title product as a dark yellow oil (5.0g, 99%): ¹H NMR (CDC₁₃) δ 0.21 (s, 9H), 0.28 (s, 9H), 4.55 (d, 1H), 4.79(d, 1H), 5.08 (s, 2H), 6.56 (d, 1H), 7.12 (t, 1H), 7.24 (d, 1H), 7.42(d, 1H), 7.65 (d, 1H), 7.82 (s, 1H).

Example 102 Synthesis of3-(3-{[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-hydroxy-methyl}-phenyl)-4H-[1,2,4]oxadiazol-5-one

Add isopropyl magnesium chloride (2M solution in tetrahydrofuran, 1.01mL, 2.02 mmol) to a solution of2-chloro-1-(3-iodo-benzyloxy)-3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-benzene(1.00 g, 1.83 mmol) in tetrahydrofuran (0.1M) chilled to 0° C. After 15minutes, warm to room temperature. After 1 hour, cool to −78° C. Addsodium hydride (60% dispersion, 80 mg, 2.01 mmol) to a solution of3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzaldehyde (348 mg, 1.83mmol) in tetrahydrofuran (0.1 M). Sonicate the solution for 5 minutesthen add it via syringe to the gringard reagent. After 30 minutes, warmthe reaction to room temperature. Quench with 10% aq hydrochloric acid.Pour the reaction into brine and extract with 25% isopropyl alcohol:75%dichloromethane. Combine the organic layers, dry with sodium sulfate,filter and concentrate under reduced pressure to give a residue. Purifythe residue by flash chromatography eluting with ethylacetate:hexanes:acetic acid (50%:50%:0.1%) to yield the title product asa white solid (120 mg, 14%): ¹H NMR (DMSO-d₆) δ 2.61 (s, 3H), 5.32 (s,2H), 5.79 (d, 1H), 6.15 (d, 1H), 6.87 (d, 1H), 7.32-7.41 (m, 3H), 7.49(m, 2H), 7.59 (dt, 1H), 7.64 (dt, 1H), 7.89-7.92 (m, 2H), 12.96 (bs,1H), 13.13 (s, 1H); MS (esi negative) m/z (rel intensity) 465 (100).

Preparation 136 Synthesis of 5-bromo-N-methoxy-N-methyl-nicotinamide

Heat a solution of 5-bromo-nicotinic acid (50 g, 248 mmol) in thionylchloride (200 mL) to reflux. After 4 hours, cool to ambient temperatureand concentrate under reduced pressure to give a residue. Dissolveresidue in dichloromethane (1.0 L). Add pyridine (58.7 g, 743 mmol)followed by O,N-dimethyl-hydroxylamine hydrochloride (26.6 g, 272 mmol)and stir. After 18 hours, add water (1.0 L) and extract withdichloromethane. Combine the organic layers, dry with sodium sulfate,filter and concentrate under reduced pressure to yield the title productas a clear oil (59.1 g, 97%):¹H NMR (DMSO-d₆) δ 3.29 (bs, 3H), 3.57 (bs,3H), 8.24 (dd, 1H), 8.75 (d, 1H), 8.83 (d, 1H).

Preparation 137 Synthesis of(5-bromo-pyridin-3-yl)-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-methanone

Add n-butyllithium (4.56 mL, 7.30 mmol) to a solution of(4-bromo-benzyloxy)-tert-butyl-dimethyl-silane (2.0 g, 6.64 mmol) intetrahydrofuran (60 mL) cooled to −78° C. After 2 hours, add5-bromo-N-methoxy-N-methyl-nicotinamide (1.63 g, 6.64 mmol), and allowsolution to warm gradually to ambient temperature. After 2 hours, add 1%aqueous hydrochloric acid (60 mL) and stir. After 20 minutes, extractsolution with ethyl acetate. Combine the organic layers, dry with sodiumsulfate, filter and concentrate under reduced pressure to give aresidue. Purify the residue by flash chromatography eluting with 12.5%ethyl acetate:hexanes to yield the title product as a white solid (1.10g, 41%): ¹H NMR (DMSO-d₆) δ 0.11 (s, 6H), 0.93 (s, 9H), 4.84 (bs, 2H),7.52 (d, 2H), 7.79 (d, 2H), 8.31 (t, 1H), 8.82 (d, 1H), 8.98 (d, 1H).

Preparation 138 Synthesis of5-[4-(tert-butyl-dimethyl-silanyloxymethyl)-benzoyl]-nicotinonitrile

Add tetrakis(triphenylphosphine)palladium (284 mg, 0.246 mmol) to asolution of(5-bromo-pyridin-3-yl)-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-methanone(1.0 g, 2.46 mmol) and zinc cyanide (578 mg, 4.92 mmol) indimethylformamide (25 mL) and stir. Purge solution with nitrogen andheat to 80° C. After 18 hours, add water (100 mL) and extract with ethylacetate. Combine the organic layers, dry with sodium sulfate, filter andconcentrate under reduced pressure to give a residue. Purify the residuewith flash chromatography eluting with 12.5% ethyl acetate:hexanes toyield the title product as a white solid (550 mg, 63%): ¹H NMR (DMSO-d₆)δ 0.11 (s, 6H), 0.93 (s, 9H), 4.84 (bs, 2H), 7.53 (d, 2H), 7.83 (d, 2H),8.61 (t, 1H), 9.09 (d, 1H), 9.26 (d, 1H).

Preparation 139 Synthesis of 5-(4-hydroxymethyl-benzoyl)-nicotinonitrile

Dissolve5-[4-(tert-butyl-dimethyl-silanyloxymethyl)-benzoyl]-nicotinonitrile(510 mg, 1.45 mmol) in 10% aqueous hydrochloric acid (10 mL) andtetrahydrofuran (50 mL) and stir. After 1 hour, add saturated aqueoussodium bicarbonate (50 mL) and extract with ethyl acetate. Combine theorganic layers, dry with sodium sulfate, filter and concentrate underreduced pressure to yield the title product as a white solid (325 mg,94%): ¹H NMR (DMSO-d₆) δ 4.64 (d, 2H), 5.44 (t, 1H), 7.53 (d, 2H), 7.80(d, 2H), 8.59 (t, 1H), 9.09 (d, 1H), 9.27 (d, 1H).

Preparation 140 Synthesis of5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinonitrile

The title compound is prepared essentially as described in Preparation14 employing 5-(4-hydroxymethyl-benzoyl)-nicotinonitrile (325 mg, 1.36mmol) to afford the title compound as an white solid (448 mg, 79%): ¹HNMR (DMSO-d₆) δ 0.90 (t, 3H), 1.52 (sextet, 2H), 2.58 (s, 3H), 2.64 (t,2H), 5.41 (bs, 2H), 6.74 (d, 1H), 7.66 (d, 2H), 7.83 (d, 1H), 7.89 (d,2H), 8.62 (t, 1H), 9.11 (d, 1H), 9.27 (d, 1H), 12.86 (s, 1H).

Example 103 Synthesis of1-(2-hydroxy-3-propyl-4-{4-[5-(2H-tetrazol-5-yl)-pyridine-3-carbonyl]-benzyloxy}-phenyl)-ethanone

Using the general procedure of Example 1 using5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinonitrile(448 mg, 1.08 mmol), sodium azide (703 mg, 10.8 mmol), and triethylaminehydrochloride (1.49 g, 10.8 mmol) to yield the title product as a whitesolid (338 mg, 66%): ¹H NMR (DMSO-d₆) δ 0.90 (t, 3H), 1.53 (sextet, 2H),2.59 (s, 3H), 2.64 (t, 2H), 5.43 (s, 2H), 6.76 (d, 1H), 7.67 (d, 2H),7.84 (d, 1H), 7.92 (d, 2H), 8.68 (t, 1H), 9.05 (d, 1H), 9.46 (d, 1H),12.86 (s, 1H); MS (esi negative) m/z (rel intensity) 456 (100).

Example 104 Synthesis of5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinic acid

Add lithium hydroxide (289 mg, 12.06 mmol) to a solution of5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinonitrile(500 mg, 1.21 mmol) in dioxane (10 mL) and water (10 mL) and stir. Heatsolution to reflux. After 1 hour cool to ambient temperature, add water(100 mL) and wash with ethyl acetate. Acidify with 10% aqueoushydrochloric acid (15 mL), and extract with ethyl acetate. Combineorganic layers, dry with sodium sulfate, filter and concentrate underreduced pressure to give a residue. Purify residue by sonicating inether for 1 hour. Filter the resulting precipitate to yield the titlecompound as a beige solid (262 mg, 50%): ¹H NMR (DMSO-d₆) δ 0.86 (t,3H), 1.48 (sextet, 2H), 2.54 (s, 3H), 2.59 (t, 2H), 5.38 (s, 2H), 6.70(d, 1H), 7.62 (d, 2H), 7.79 (d, 1H), 7.84 (d, 2H), 8.42 (s, 1H), 9.05(s, 1H), 9.24 (s, 1H), 12.82 (s, 1H), 13.72 (bs, 1H); MS (esi negative)m/z (rel intensity) 432 (100).

Preparation 141 Synthesis of5-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-nicotinonitrile

Add zinc dust (5.00 g, 76.5 mmol) to a solution of5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinonitrile(4.50 g, 10.9 mmol) in acetic acid (70 ml) and stir vigorously. After 1hour, cool reaction in an ice bath and add 1N hydrochloric acid (200ml). Extract with ethyl acetate. Combine the organic layers, dry withsodium sulfate, filter, and concentrate under reduced pressure to give aresidue. Purify the residue by flash chromatography eluting withacetone:hexanes to yield the title product as a white solid (2.80 g,62%): ¹H NMR (DMSO-d₆) δ 0.86 (t, 3H), 1.47 (sextet, 2H), 2.56 (m, 5H),5.22 (s, 2H), 5.88 (m, 1H), 6.32 (d, 1H), 6.71 (d, 1H), 7.44 (q, 4H),7.79 (d, 1H), 8.27 (t, 1H), 8.88 (dd, 1H), 12.84 (s, 1H).

Example 105 Synthesis of1-[2-hydroxy-4-(4-{hydroxy-[5-(2H-tetrazol-5-yl)-pyridin-3-yl]-methyl}-benzyloxy)-3-propyl-phenyl]-ethanone

Using the general procedure of Example 1 using5-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-nicotinonitrile(473 mg, 1.14 mmol), sodium azide (738 mg, 11.4 mmol), and triethylaminehydrochloride (1.56 g, 11.4 mmol) to yield the title product as a whitesolid (170 mg, 33%): ¹H NMR (DMSO-d₆) δ 0.85 (t, 3H), 1.35 (s, 1H), 1.47(sextet, 2H), 2.56 (m, 5H), 5.22 (bs, 2H), 5.93 (d, 1H), 6.29 (d, 1H),6.71 (d, 1H), 7.45 (q, 4H), 7.78 (d, 1H), 8.39 (t, 1H), 8.77 (d, 1H),9.07 (d, 1H), 12.83 (s, 1H); MS (esi negative) m/z (rel intensity) 458(100).

Example 106 Synthesis of5-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-nicotinicacid

Add lithium hydroxide (1M aqueous solution, 11.4 mL, 11.4 mmol) to asolution of5-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-nicotinonitrile(473 mg, 1.14 mmol) in dioxane (10 mL). Heat reaction to 80° C. After 2hours, cool to room temperature and pour into water (50 ml). Washsolution with ethyl acetate (25 mL), and discard. Acidify the aqueouslayer with 10% hydrochloric acid, and extract with 25% isopropylalcohol:75% dichloromethane. Combine the organic layers, dry with sodiumsulfate, filter and concentrate under reduced pressure to give aresidue. Sonicate the residue in acetonitrile (10 mL), and filter toyield the title compound as a beige solid (210 mg, 42%): ¹H NMR(DMSO-d₆) δ 0.86 (t, 3H), 1.47 (sextet, 2H), 2.55-2.59 (m, 5H), 5.22(bs, 2H), 5.90 (bs, 1H), 6.70 (d, 1H), 7.43 (q, 4H), 7.79 (d, 1H), 8.21(t, 1H), 8.82 (d, 1H), 8.92 (d, 1H), 12.84 (s, 1H); MS (esi negative)m/z (rel intensity) 434 (100).

Preparation 142 Synthesis of 2-hydroxymethyl-isonicotinonitrile

Add ammonium persulfate (70.1 g, 307 mmol) to a solution ofisonicotinonitrile (16.00 g, 154 mmol) in methanol:water:sulfuric acid(275 mL: 135 mL: 11 mL). Heat solution to reflux. After 24 hours, pourreaction onto ice and neutralize with ammonium hydroxide (70 ml).Extract solution with chloroform (3×600 ml). Combine the organic layers,dry with sodium sulfate, filter, and concentrate under reduced pressureto give a residue. Purify the residue by flash chromatography elutingwith acetone:dichloromethane (1:6) to yield the title compound as awhite solid (5.86 g, 28%): ¹H NMR (CDC₁₃) δ 3.17 (t, 1H), 4.84 (d, 1H),7.45 (m, 1H), 7.58 (s, 1H), 8.74 (d, 1H).

Preparation 143 Synthesis of 2-formyl-isonicotinonitrile

Add selenium dioxide (2.69 g, 24.2 mmol) to a solution of2-hydroxymethyl-isonicotinonitrile (5.86 g, 43.7 mmol) in dioxane (120mL). Heat reaction to 80° C. After 4 hours, cool to room temperature.Add dichloromethane (500 mL) and celite and stir. After 15 minutes,filter through a plug of silica eluting with dichloromethane.Concentrate filtrate under reduced pressure to yield the title compoundas an orange solid (5.30 g, 92%): ¹H NMR (DMSO-d₆) δ 8.19 (dd, 1H), 8.34(t, 1H), 9.07 (dd, 1H), 10.01 (s, 1H).

Preparation 144 Synthesis of2-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-isonicotinonitrile

Add isopropyl magnesium chloride (2M solution in tetrahydrofuran, 2.98mL, 5.95 mmol) to a solution of1-(4-iodo-benzyloxy)-2-propyl-3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-benzene(3.00 g, 5.41 mmol) in tetrahydrofuran (0.1M) cooled to 0° C. After 15minutes, warm reaction to room temperature. After 1 hour, cool thereaction to −78° C. Add a solution of 2-formyl-isonicotinonitrile (612mg, 5.95 mmol) in tetrahydrofuran (10 mL) via syringe. After 1 hour,warm the reaction to room temperature. Add 10% hydrochloric acid (30mL). After 5 minutes, pour the reaction into water and extract withethyl acetate. Combine organics, dry with sodium sulfate, filter andconcentrate under reduced pressure to give a residue. Purify the residueby flash chromatography eluting with methanol:dichlormethane followed bytrituration with acetonitrile to yield the title product as a whitesolid (1.71 g, 76%): ¹H NMR (CDC₁₃) δ 0.95 (t, 3H), 1.56 (sextet, 2H),2.56 (s, 3H), 2.69 (t, 2H), 4.50 (d, 1H), 5.16 (s, 2H), 5.84 (d, 1H),6.46 (d, 1H), 7.41 (m, 4H), 7.51 (s, 1H), 7.55 (d, 1H), 8.76 (d, 1H),12.74 (s, 1H).

Example 107 Synthesis of2-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-isonicotinicacid

Add lithium hydroxide (2M aqueous solution, 20.4 mL, 40.8 mmol) to asolution of2-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-isonicotinonitrile(1.70 g, 4.08 mmol) in dioxane (40 mL) and stir. Heat the reaction toreflux. After 4 hours, cool reaction to room temperature, acidify with1N hydrochloric acid and extract with ethyl acetate. Combine organiclayers, dry with sodium sulfate, filter and concentrate under reducedpressure to give a residue. Sonicate the residue in acetonitrile andfilter to yield the title product as a beige solid (1.60 g, 90%): ¹H NMR(DMSO-d₆) δ 0.86 (t, 3H), 1.46 (sextet, 2H), 2.56 (m, 5H), 5.21 (s, 2H),5.82 (s, 1H), 6.69 (d, 1H), 7.41 (m, 4H), 7.68 (dd, 1H), 7.78 (d, 1H),8.04 (s, 1H), 8.64 (d, 1H), 12.83 (s, 1H); MS (esi negative) m/z (relintensity) 434 (100).

Preparation 145 Synthesis of 3-(4-hydroxymethyl-benzyl)-benzoic acidmethyl ester

Tetrakis(triphenylphosphine)palladium(0) (550 mg, 0.476 mmol) is addedto a mixture of 3-bromomethyl-benzoic acid methyl ester (3.0 g, 13.09mmol) and 4-(hydroxymethyl)-phenylboronic acid (2.99 g, 19.68 mmol) in amixture of toluene (125 mL) and 2M sodium carbonate (62 mL). The mixturewas degassed, placed under nitrogen and heated at 85° C. for 16 hours.After cooling to room temperature, the mixture is concentrated in vacuoand the black residue is partitioned between saturated sodiumbicarbonate and dichloromethane. After the layers are separated, theaqueous layer is extracted two more times with dichloromethane. Thecombined organic layers are washed with brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue is purified byflash chromatography (20% tetrahydrofuran in hexanes) to give 2.71 g ofthe title compound as a yellow oil: MS (m/z): 239 (M−OH); ¹H NMR (CDC₁₃)δ 7.92 (m, 2H), 7.42-7.36 (m, 2H), 7.34-7.29 (m, 2H), 7.21 (d, J=8.0 Hz,2H), 4.69 (s, 2H), 4.05 (s, 2H), 3.93 (s, 3H), 1.79 (s, 1H).

The following compounds are prepared by an analogous procedure forcoupling as described in Preparation 145.

Preparation 146 4-(3-hydroxymethyl-benzyl)-benzoic acid methyl ester: MS(m/z): 239 (M−OH) Preparation 147 3-(3-hydroxymethyl-benzyl)-benzoicacid methyl ester: MS (m/z): 239 (M−OH) Preparation 1484-(4-hydroxymethyl-benzyl)-benzoic acid methyl ester: MS (m/z): 239(M−OH) Preparation 149 3-[(4-hydroxymethyl-benzyl)-benzonitrile: MS(m/z): 206 (M−OH) Preparation 150 Synthesis of3-(4-Iodomethyl-benzyl)-benzoic acid methyl ester

The resin-bound triphenylphosphine (7.59 g, 22.77 mmol), iodine (5.79 g,22.81 mmol) and imidazole (1.55 g, 22.76 mmol) in dichloromethane (65mL) are gently stirred for 1 hour at room temperature. A solution ofalcohol of preparation 284 (2.92 g, 11.39 mmol) in dichloromethane (65mL) is then added, and stirring is continued for another 1 hour. Thesolids are removed by filtration through Celite. The mother liquor iswashed with saturated sodium bisulfite, water, and brine, then driedover magnesium sulfate, filtered and concentrated in vacuo to give thetitle compound as a yellow solid: ¹H NMR δ (CDC₁₃); 9.24 (m, 2H), 7.39(m, 2H), 7.36-7.32 (m, 2H), 7.14 (d, J=8.0 Hz, 2H), 4.47 (s, 2H), 4.02(s, 2H), 3.94 (s, 3H).

The following compounds are prepared by an analogous procedure asdescribed in Preparation 150.

Preparation 151 4-(3-iodomethyl-benzyl)-benzoic acid methyl ester: MS(m/z): 239 (M−1) Preparation 152 3-[(4-iodomethyl-benzyl)]-benzonitrile:MS (m/z): 206 (M−1) Preparation 153 3-(3-iodomethyl-benzyl)-benzoic acidmethyl ester: MS (m/z): 239 (M−1) Preparation 1544-(4-iodomethyl-benzyl)-benzoic acid methyl ester: MS (m/z): 239 (M−1)Preparation 155 Synthesis of3-[4-(4-acetyl-3-hydroxy-2-iodo-phenoxymethyl)-benzyl]-benzoic acidmethyl ester

Potassium carbonate (675 mg, 4.88 mmol) is added to a solution of4-acetyl-3-hydroxy-2-iodo-phenol (925 mg, 3.33 mmol) and3-(4-iodomethyl-benzyl)-benzoic acid methyl ester (1.21 g, 3.30 mmol) inacetone (65 mL). The resulting suspension is heated at 50° C. for 16hours. The reaction mixture is cooled to room temperature andconcentrated in vacuo. The residue is taken up in dichloromethane,washed with 1N hydrochloric acid, brine, dried over magnesium sulfate,filtered and concentrated to give a yellow solid. This solid isdissolved in dichloromethane and a white precipitate forms upon additionof ethyl acetate. The white solid is filtered off and the mother liquoris purified by flash chromatography, eluting with 20% ethyl acetate inhexanes. The precipitate and chromatographed materials are combined togive 1.04 g of the title compound as a pale yellow solid: MS (m/z) 517(M+1), 515 (M−1); ¹H NMR δ (CDC₁₃); 13.58 (s, 1H), 7.93 (m, 2H), 7.74(d, J=9.0 Hz, 1H), 7.45-7.38 (m, 4H), 7.25 (d, J=8.0 Hz, 2H), 6.50 (d,J=9.0 Hz, 1H), 5.27 (s, 2H), 4.07 (s, 2H), 3.94 (s, 3H), 2.63 (s, 3H).

The following compounds are prepared by an analogous procedure asdescribed in Preparation 155.

Preparation 1563-{[4-(4-acetyl-3-hydroxy-2-iodo-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile:MS (m/z) 500 (M+1) Preparation 1573-[4-(4-acetyl-3-hydroxy-2-iodo-phenoxymethyl)-benzyl]-benzonitrile: MS(m/z) 484 (M+1) Preparation 158 Synthesis of3-[4-(4-acetyl-3-hydroxy-2-pyridin-2-yl-phenoxymethyl)-benzyl]-benzoicacid methyl ester

A mixture of3-[4-(4-acetyl-3-hydroxy-2-iodo-phenoxymethyl)-benzyl]-benzoic acidmethyl ester (417 mg, 0.808 mmol), 2-tributylstannanyl-pyridine (1.72 g,4.67 mmol), and tetrakis(triphenylphosphine)palladium(0) (111 mg, 0.096mmol) in toluene (19 mL) is thoroughly degassed, placed under nitrogenand heated at 100° C. for 16 hours. After cooling to room temperature,the reaction mixture is concentrated in vacuo. The residue thus obtainedis purified by flash chromatography (20% to 40% ethylacetate in hexanes)to give 230 mg of the title compound as a yellow oil: MS (m/z): 468(M+1); ¹H NMR (CDC₁₃) δ 8.74 (m, 1H), 7.87 (m, 2H), 7.78 (m, 2H), 7.56(d, J=8.0 Hz, 1H), 7.36-7.27 (m, 3H), 7.17 (d, J=8.0 Hz, 2H), 7.11 (d,J=8.0 Hz, 2H), 6.60 (d, J=9.0 Hz, 1H), 5.14 (s, 2H), 3.99 (s, 2H), 3.89(s, 3H), 2.61 (s, 3H).

The following compounds are prepared by an analogous procedure asdescribed in Preparation 158.

Preparation 1593-[4-(4-acetyl-3-hydroxy-2-pyridin-2-yl-phenoxymethyl)-benzyl]-benzoicacid methyl ester: MS (m/z) 468 (M+1) Preparation 1603-[4-(4-acetyl-3-hydroxy-2-pyridin-3-yl-phenoxymethyl)-benzyl]-benzoicacid methyl ester: MS (m/z) 468 (M+1) Preparation 1613-[4-(4-acetyl-3-hydroxy-2-pyridin-4-yl-phenoxymethyl)-benzyl]-benzoicacid methyl ester: MS (m/z) 468 (M+1) Preparation 1623-{[4-(4-acetyl-3-hydroxy-2-thiazol-2-yl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile:MS (m/z) 457 (M+1) Preparation 1633-[4-(4-acetyl-3-hydroxy-2-thiophen-2-yl-phenoxymethyl)-benzyl]-benzoicacid methyl ester: MS (m/z) 473 (M+1) Preparation 1644-[4-(4-acetyl-3-hydroxy-2-thiophen-2-yl-phenoxymethyl)-benzyl]-benzoicacid methyl ester: MS (m/z) 473 (M+1) Preparation 1653-[3-(4-acetyl-3-hydroxy-2-thiophen-2-yl-phenoxymethyl)-benzyl]-benzoicacid methyl ester: MS (m/z) 473 (M+1) Preparation 1664-[3-(4-acetyl-3-hydroxy-2-thiophen-2-yl-phenoxymethyl)-benzyl]-benzoicacid methyl: MS (m/z) 473 (M+1) Preparation 1673-[4-(4-Acetyl-3-hydroxy-2-thiazol-2-yl-phenoxymethyl)-benzyl]-benzoicacid methyl ester: MS (m/z) 474 (M+1) Examples 107-123

The Examples in the following table are prepared essentially asdescribed initially in Preparation 158, followed by an analogousprocedure described in Example 1 for compounds of formula I where Z istetrazolyl or an analogous procedure described Example 35 for compoundsof formula I where Z is carboxylic acid.

Ex. No. Chemical Name Structure Physical Data 107 3-[4-(4-Acetyl-3-hydroxy-2-thiophen- 2-yl-phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.46 (s, 1 H), 12.79 (bs, 1 H), 7.93 (d, J = 8.8 Hz,1 H), 7.77-7.73 (m, 2 H), 7.54 (dd, J = 5.0 Hz and 1.0 Hz, 1 H),7.49-7.37 (m, 4 H), 7.33 (m, 1 H), 7.23 (m, 2 H), 7.08-7.05 (m, 1 H),6.84 (d, J = 9.0 Hz, 1 H), 5.27 (s, 2 H), 3.99 (s, 2 H), 2.60 (s, 3 H);MS (m/e): 459 (M + 1). 108 4-[4-(4-Acetyl-3- hydroxy-2-thiophen-2-yl-phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.45 (s, 1 H), 12.78 (s, 1 H), 7.93 (d, J = 9.3 Hz,1 H), 7.84 (m, 2 H), 7.55 (m, 1 H), 7.44 (m, 1 H), 7.33 (m, 4 H), 7.23(d, J = 8.0 Hz, 2 H), 7.08-7.05 (m, 1 H), 6.84 (d, J = 9.0 Hz, 1 H),5.27 (s, 2 H), 3.99 (s, 2 H), 2.60 (s, 3 H); MS (m/e): 459 (M + 1). 1093-[3-(4-Acetyl-3- hydroxy-2-thiophen- 2-yl-phenoxymethyl)-benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.45 (s, 1 H), 12.91 (s, 1 H), 7.93 (d, J = 9.0 Hz,1 H), 7.76 (m, 2 H), 7.52 (m, 1 H), 7.46-7.37 (m, 3 H), 7.31-7.19 (m, 4H), 7.04 (m, 1 H), 6.84 (d, J = 9.0 Hz, 1 H), 5.26 (s, 2 H), 3.99 (s, 2H), 2.61 (s, 3 H); MS (m/e): 459 (M + 1). 110 4-[3-(4-Acetyl-3-hydroxy-2-thiophen- 2-yl-phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.45 (s, 1 H) 12.79 (bs, 1 H), 7.93 (d, J = 9.0 Hz,1 H), 7.84 (d, J = 8.2 Hz, 2 H), 7.52 (m, 1 H), 7.39 (m, 1 H), 7.31-7.18(m, 6 H), 7.04 (m, 1 H), 6.83 (d, J = 9.2 Hz, 1 H), 5.26 (s, 2 H), 3.98(s, 2 H), 2.61 (s, 3 H); MS (m/e): 459 (M + 1). 111 1-(2-Hydroxy-3-pyridin-2-yl-4-{4-[3- (2H-tetrazol-5-yl)- benzyl]-benzyloxy}-phenyl)-ethanone

¹H NMR (DMSO-d₆) δ 13.09 (s, 1 H), 8.62 (m, 1 H), 7.95-7.78 (m, 4 H),7.51-7.41 (m, 3 H), 7.31 (m, 2 H), 7.23-7.17 (m, 4 H), 6.79 (d, J = 9.3Hz, 1 H), 5.17 (s, 2 H), 4.0 (s, 2 H), 2.59 (s, 3 H); MS (m/e): 478 (M +1). 112 1-(2-Hydroxy-4-{4- [3-(2H-tetrazol-5-yl)- benzyl]-benzyloxy}-3-thiophen-2-yl- phenyl)-ethanone

¹H NMR (DMSO-d₆) δ 13.46 (s, 1 H), 7.92 (m, 2 H), 7.83 (m, 1 H),7.55-7.42 (m, 4 H), 7.34 (d, J = 7.1 Hz, 2 H), 7.27 (d, J = 8.2 Hz, 2H), 7.06 (m, 1 H), 6.84 (d, J = 8.2 Hz, 1 H), 5.27 (s, 2 H), 4.03 (s, 2H), 2.60 (s, 3 H); MS (m/e): 483 (M + 1). 113 3-[4-(4-Acetyl-2-cyano-3-hydroxy- phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 12.86 (bs, 1 H), 12.58 (s, 1 H), 7.83-7.73 (m, 3 H),7.48 (d, J = 7.5 Hz, 1 H), 7.42-7.34 (m, 3 H), 7.25 (d, J = 8.0 Hz, 2H), 6.57-6.51 (m, 2 H), 5.12 (s, 2 H), 4.0 (s, 2 H), 2.53 (s, 3 H); MS(m/e): 375 (M − CN). 114 3-[4-(4-Acetyl-3- hydroxy-2-pyridin-4-yl-phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.2 (s, 1 H), 8.87-8.85 (m, 2 H), 8.12 (d, J = 9.0Hz, 1 H), 8.02 (d, J = 6.8 Hz, 2 H), 7.76-7.73 (m, 2 H), 7.48-7.45 (m, 1H), 7.42-7.37 (m, 1 H), 7.27-7.19 (m, 4 H), 6.94 (d, J = 9.2 Hz, 1 H),5.24 (s, 2 H), 3.98 (s, 2 H), 2.63 (s, 3 H); MS (m/e): 454 (M + 1). 1153-[4-(4-Acetyl-3- hydroxy-2-pyridin-2- yl-phenoxymethyl)-benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.12 (bs, 1 H), 8.9 (d, J = 5.2 Hz, 1 H), 8.47 (m, 1H), 8.16 (d, J = 9.2 Hz, 1 H), 8.0 (d, J = 7.7 Hz, 1 H), 7.88 (m, 1 H),7.75-7.73 (m, 2 H), 7.46 (m, 1 H), 7.41-7.36 (m, 1 H), 7.25-7.17 (m, 4H), 6.95 (d, J = 9.0 Hz, 1 H), 5.24 (s, 2 H), 3.97 (s, 2 H), 2.64 (s, 3H); MS (m/e): 454 (M + 1). 116 3-[4-(4-Acetyl-3- hydroxy-2-thiazol-2-yl-phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 12.85 (bs, 1 H), 8.03 (d, J = 3.6 Hz, 1 H), 7.85 (d,J = 3.5 Hz, 1 H), 7.79-7.74 (m, 3 H), 7.50-7.38 (m, 4 H), 7.28 (d, J =8.0 Hz, 2 H), 6.92 (d, J = 9.0 Hz, 1 H), 5.42 (s, 2 H), 4.02 (s, 2 H),2.60 (s, 3 H); MS (m/e): 460 (M + 1). 117 3-[4-(4-Acetyl-3-hydroxy-2-pyridin-3- yl-phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 12.93 (s, 1 H), 8.52 (s, 1 H), 8.48 (d, J = 5.0 Hz, 1H), 8.0 (d, J = 9.2 Hz, 1 H), 7.78-7.73 (m, 3 H), 7.47-7.36 (m, 3 H),7.20 (s, 4 H), 6.86 (d, J = 9.2 Hz, 1 H), 5.18 (s, 2 H), 3.97 (s, 2 H),2.61 (s, 3 H); MS (m/e): 454 (M + 1). 118 4-[4-(4-Acetyl-3-hydroxy-2-pyridin-4- yl-phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.24 (s, 1 H), 8.88 (m, 2 H), 8.13 (d, J = 9.3 Hz, 1H), 8.05 (m, 2 H), 7.83 (m, 2 H), 7.32 (d, J = 8.3 Hz, 2 H), 7.27-7.19(m, 4 H), 6.99 (d, J = 9.3 Hz, 1 H), 5.24 (s, 2 H), 3.98 (s, 2 H), 2.63(s, 3 H); MS (m/e): 454 (M + 1). 119 3-[3-(4-Acetyl-3-hydroxy-2-pyridin-4- yl-phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.20 (s, 1 H), 8.83 (dd, J = 6.6 Hz and 1.3 Hz, 2H), 8.1 (d, J = 9.3 Hz, 1 H), 7.94 (d, J = 6.5 Hz, 2 H), 7.75 (m, 2 H),7.45-7.37 (m, 2 H), 7.27 (m, 1 H), 7.16 (m, 3 H), 6.92 (d, J = 9.0 Hz, 1H), 5.24 (s, 2 H), 3.97 (s, 2 H), 2.64 (s, 3 H); MS (m/e): 454 (M + 1).120 4-[3-(4-Acetyl-3- hydroxy-2-pyridin-4- yl-phenoxymethyl)-benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.23 (s, 1 H), 8.88 (d, J = 6.5 Hz, 2 H), 8.12 (d, J= 9.0 Hz, 1 H), 8.01 (d, J = 6.5 Hz, 2 H), 7.84 (d, J = 8.2 Hz, 2 H),7.29-7.24 (m, 3 H), 7.18-7.14 (m, 3 H), 6.92 (d, J = 9.0 Hz, 1 H), 5.24(s, 2 H), 3.97 (s, 2 H), 2.64 (s, 3 H); MS (m/e): 454 (M + 1). 1211-(2-Hydroxy-3- pyridin-4-yl-4-{4-[3- (2H-tetrazol-5-yl)-benzyl]-benzyloxy}- phenyl)-ethanone

¹H NMR (DMSO-d₆) δ 12.96 (s, 1 H), 8.65 (bs, 1 H), 8.01 (d, J = 9.0 Hz,1 H), 7.90 (s, 1 H), 7.83 (d, J = 7.1 Hz, 1 H), 7.52-7.42 (m, 5 H), 7.23(s, 5 H), 6.86 (d, J = 9.0 Hz, 1 H), 5.20 (s, 2 H), 4.01 (s, 2 H), 2.60(s, 3 H); MS (m/e): 478 (M + 1). 122 1-(2-Hydroxy-3-pyridin-3-yl-4-{4-[3- (2H-tetrazol-5-yl)- benzyl]-benzyloxy}-phenyl)-ethanone

¹H NMR (DMSO-d₆) δ 12.98 (s, 1 H), 8.66-8.53 (m, 2 H), 8.03 (d, J = 9.0Hz, 1 H), 7.96 (d, J = 7.5 Hz, 1 H), 7.89 (s, 1 H), 7.83 (d, J = 7.5 Hz,1 H), 7.61-7.42 (m, 3 H), 7.23 (m, 4 H), 6.88 (d, J = 9.0 Hz, 1 H), 5.20(s, 2 H), 4.01 (s, 2 H), 2.61 (s, 3 H); MS (m/e): 478 (M + 1). 1231-(2-Hydroxy-3- pyridin-2-yl-4-{4-[3- (2H-tetrazol-5-yl)-benzyl]-benzyloxy}- phenyl)-ethanone

¹H NMR (DMSO-d₆) δ 13.09 (s, 1 H), 8.62 (m, 1 H), 7.95-7.78 (m, 4 H),7.51-7.41 (m, 3 H), 7.31 (m, 2 H), 7.23-7.17 (m, 4 H), 6.79 (d, J = 9.3Hz, 1 H), 5.17 (s, 2 H), 4.0 (s, 2 H), 2.59 (s, 3 H); MS (m/e): 478 (M +1).

Examples 124-126

The examples in the following table are prepared by an analogousprocedure for coupling as described in Preparation 158 followed by ananalogous procedure for ester hydrolysis as described Example 35.

Ex. No. Chemical Name Structure Physical Data 124 3-{[4-(4-Acetyl-3-hydroxy-2-thiazol-2- yl-phenoxymethyl)- phenyl]-hydroxy- methyl}-benzoicacid

¹H NMR (DMSO-d₆) 8.03 (d, J = 3.0 Hz, 1 H), 7.95-7.92 (m, 1 H), 7.85 (d,J = 3.5 Hz, 1 H), 7.81-7.74 (m, 2 H), 7.62-7.57 (m, 1 H), 7.50-7.46 (m,2 H), 7.44-7.37 (m, 3 H), 6.91 (d, J = 9.2 Hz, 1 H), 6.05-6.00 (bs, 1H), 5.78 (s, 1 H), 5.42 (s, 2 H), 2.59 (s, 3 H); MS (m/e): 474 (M − 1).125 3-{[4-(4-Acetyl-3- hydroxy-2-pyridin-3- yl-phenoxymethyl)-phenyl]-hydroxy- methyl}-benzoic acid

¹H NMR (DMSO-d₆) δ 12.9 (s, 1 H), 8.71-8.53 (m, 2 H), 8.06-7.97 (m, 2H), 7.93-7.89 (m, 1 H), 7.79-7.73 (m, 1 H), 7.64-7.54 (m, 2 H),7.44-7.36 (m, 1 H), 7.36-7.29 (m, 2 H), 7.26-7.18 (m, 2 H), 6.87 (d, J =9.2 Hz, 1 H), 5.73 (s, 1 H), 5.19 (s, 2 H), 2.61 (s, 3 H); MS (m/e): 468(M − 1). 126 3-{[4-(4-Acetyl-3- hydroxy-2-pyridin-4- yl-phenoxymethyl)-phenyl]-hydroxy- methyl}-benzoic acid

¹H NMR (DMSO-d₆) δ 8.60 (bs, 2 H), 8.03 (d, J = 9.2 Hz, 1 H), 7.98-7.92(bs, 1 H), 7.79 (d, J = 7.5 Hz, 1 H), 7.60 (d, J = 7.9 Hz, 1 H),7.47-7.33 (m, 5 H), 7.29-7.23 (m, 2 H), 6.87 (d, J = 9.2 Hz, 1 H), 6.02(bs, 1 H), 5.76 (s, 1 H), 5.22 (s, 2 H), 2.63 (s, 3 H); MS (m/e): 468 (M− 1).

Examples 127-131

The examples in the following table are prepared by an analogousalkylation procedure as in described in Preparation 155. Followed by,for compounds of formula I where Z is tetrazolyl, the examples areprepared by an analogous procedure as described in Example 1 or, forcompounds of formula I where Z is carboxylic acid, the examples areprepared by an analogous procedure for deprotection as described inPreparation 33 followed by an analogous procedure for ester hydrolysisas described Example 35.

Ex. No. Chemical name Structure Physical data 127 1-[2-Hydroxy-4-(4-{hydroxy-[3-(2H- tetrazol-5-yl)- phenyl]-methyl}- benzyloxy)-3-thiophen-3-yl- phenyl]-ethanone

¹H NMR (DMSO-d₆) δ 13.1 (s, 1 H), 8.12 (bs, 1 H), 7.94 (d, J = 9.2 Hz, 1H), 7.91-7.87 (m, 1 H), 7.60-7.48 (m, 4 H), 7.45-7.42 (m, 2 H),7.36-7.34 (m, 2 H), 7.28-7.25 (m, 1 H), 6.13-6.10 (m, 1 H), 5.83-5.80(m, 1 H), 5.23 (m, 2 H), 2.62 (m, 3 H); MS (m/e): 497 (M − 1). 1283-{[4-(4-Acetyl-3- hydroxy-2-thiophen- 3-yl-phenoxymethyl)-phenyl]-hydroxy- methyl}-benzoic acid

¹H NMR (DMSO-d₆) δ 7.96-7.93 (m, 2 H), 7.80-7.76 (m, 1 H), 7.61-7.56 (m,2 H), 7.53-7.50 (m, 1 H), 7.44-7.25 (m, 6 H), 6.83 (d, J = 9.2 Hz, 1 H),5.77 (s, 1 H), 5.23 (s, 2 H), 2.63 (s, 3 H); MS (m/e): 473 (M − 1). 1291-[2-Hydroxy-4-(4- {hydroxy-[3-(2H- tetrazol-5-yl)- phenyl]-methyl}-benzyloxy)-3- thiophen-2-yl-phenyl]- ethanone

¹H NMR (DMSO-d₆) δ 13.5 (bs, 1 H), 8.16-8.10 (bs, 1 H), 7.95 (d, J = 8.8Hz, 1 H), 7.92-7.86 (m, 1 H), 7.62-7.50 (m, 3 H), 7.49-7.36 (m, 5 H),7.14-7.07 (m, 1 H), 6.87 (d, J = 9.2 Hz, 1 H), 6.14-6.11 (m, 1 H),5.84-5.82 (m, 1 H), 5.31 (m, 2 H), 2.64 (s, 3 H); MS (m/e): 497 (M − 1).130 3-{[4-(4-Acetyl-3- hydroxy-2-thiophen- 2-yl-phenoxymethyl)-phenyl]-hydroxy- methyl}-benzoic acid

¹H NMR (DMSO-d₆) δ 13.5 (s, 1 H), 7.97-7.90 (m, 2 H), 7.79-7.73 (m, 1H), 7.62-7.58 (m, 1 H), 7.56-7.53 (m, 1 H), 7.46-7.31 (m, 6 H),7.10-7.04 (m, 1 H), 6.83 (d, J = 9.2 Hz, 1 H), 6.00 (bs, 1 H), 5.75 (s,1 H), 5.27 (s, 2 H), 2.60 (s, 3 H); MS (m/e): 473 (M − 1). 1311-[2-Hydroxy-4-(4- {hydroxy-[3-(2H- tetrazol-5-yl)- phenyl]-methyl}-benzyloxy)-3- pyridin-2-yl-phenyl]- ethanone

¹H NMR (DMSO-d₆) δ 13.1 (bs, 1 H), 8.68-8.60 (m, 1 H), 8.12-8.02 (bs, 1H), 7.97 (d, J = 9.2 Hz, 1 H), 7.88-7.78 (m, 2 H), 7.50-7.43 (m, 3 H),7.41-7.31 (m, 3 H), 7.27-7.21 (m, 2 H), 6.82 (d, J = 9.2 Hz, 1 H), 6.03)bs, 1 H), 5.76 (s, 1 H), 5.20 (s, 2 H), 2.62 (s, 3 H); MS (m/e): 492 (M− 1).

Examples 132-141

The examples in the following table are prepared an analogous alkylationprocedure as described in Preparation 155, followed by an analogousprocedure described in Example 1 for compounds of formula I where Z istetrazolyl or an analogous procedure described Example 13 for compoundsof formula I where Z is carboxylic acid.

Ex No. Chemical Name Structure Physical Data 132 3-[4-(4-Acetyl-3-hydroxy-2-iodo- phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.5 (s, 1 H), 12.9 (bs, 1 H), 8.0 (d, J = 9.0 Hz, 1H), 7.84-7.77 (m, 2 H), 7.54 (d, J = 7.8 Hz, 1 H), 7.46-7.41 (m, 3 H),7.31 (d, J = 8.0 Hz, 2 H), 6.78 (d, J = 9.0 Hz), 5.33 (s, 2 H), 4.05 (s,2 H), 2.63 (s, 3 H); MS (m/e): 501 (M − 1). 133 3-[4-(4-Acetyl-3-hydroxy-2-propyl- phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 12.90 (bs, 1 H), 12.82 (s, 1 H), 7.79-7.73 (m, 3 H),7.49 (m, 1 H), 7.41-7.33 (m, 3 H), 7.26 (d, J = 8.0 Hz, 2 H), 6.69 (d, J= 9.0 Hz, 1 H), 5.19 (s, 2 H), 4.0 (s, 2 H), 2.54 (s, 5 H), 1.50-1.40(m, 2 H), 0.84 (t, J = 7.5 Hz, 3 H); MS (m/e): 419 (M + 1). 1344-[4-(4-Acetyl-3- hydroxy-2-propyl- phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 12.82 (s, 1 H), 12.73 (bs, 1 H), 7.85 (m, 2 H), 7.77(d, J = 9.2 Hz, 1 H), 7.36-7.32 (m, 4 H), 7.26 (d, J = 8.0 Hz, 2 H),6.69 (d, J = 9.0 Hz, 1 H), 5.19 (s, 2 H), 4.0 (s, 2 H), 2.57-2.53 (m, 5H), 1.50-1.40 (m, 2 H), 1.15 (t, J = 7.0 Hz, 3 H); MS (m/e): 419 (M +1). 135 4-[4-(4-Acetyl-3- hydroxy-2-methyl- phenoxymethyl)-benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 12.82 (s, 1 H), 12.77 (bs, 1 H), 7.84 (m, 2 H), 7.77(d, J = 9.0 Hz, 1 H), 7.38-7.32 (m, 4 H), 7.25 (d, J = 7.0 Hz, 2 H),6.70 (d, J = 9.0 Hz, 1 H), 5.20 (s, 2 H), 4.0 (s, 2 H), 2.55 (s, 3 H),2.0 (s, 3 H); MS (m/e): 389 (M − 1). 136 4-[4-(4-Acetyl-2-chloro-3-hydroxy- phenoxymethyl)- benzyl]-benzoic acid

¹H NMR (DMSO-d₆) δ 13.11 (s, 1 H), 12.83 (s, 1 H), 7.91 (d, J = 9.2 Hz,1 H), 7.74 (m, 2 H), 7.39-7.32 (m, 4 H), 7.27 (d, J = 8.2 Hz, 2 H), 6.87(d, J = 9.2 Hz, 1 H), 5.29 (s, 2 H), 4.0 (s, 2 H), 2.59 (s, 3 H); MS(m/e): 411 (M + 1). 137 1-(2-Hydroxy-3-iodo- 4-{4-[3-(2H-tetrazol-5-yl)-benzyl]- benzyloxy}-phenyl)- ethanone

¹H NMR (DMSO-d₆) δ 13.48 (s, 1 H), 7.95 (m, 2 H), 7.84 (d, J = 7.0 Hz, 1H), 7.53-7.41 (m, 4 H), 7.31 (d, J = 8.0 Hz, 2 H), 6.74 (d, J = 9.0 Hz,1 H), 5.29 (s, 2 H), 4.05 (s, 2 H), 2.59 (s, 3 H); MS (m/e): 527 (M +1). 138 4-[3-(4-Acetyl-3- hydroxy-2-propyl- phenoxymethyl)-benzyl]-benzoic acid

1 H NMR (DMSO-d₆) δ 12.82 (s, 1 H), 12.79 (s, 1 H), 7.83 (m, 2 H), 7.76(d, J = 9.0 Hz, 1 H), 7.34-7.30 (m, 3 H), 7.27-7.20 (m, 3 H), 6.67 (d, J= 9.2 Hz, 1 H), 5.18 (s, 2 H), 4.01 (s, 2 H), 2.54-2.47 (m, 5 H),1.45-1.36 (m, 2 H), 0.80 (t, J = 7.5 Hz, 3 H); MS (m/e): 419 (M + 1).139 4-[3-(4-Acetyl-3- hydroxy-2-methyl- phenoxymethyl)- benzyl]-benzoicacid

1 H NMR (DMSO-d₆) δ 12.82 (s, 1 H), 12.75 (s, 1 H), 7.84 (d, J = 8.1 Hz,2 H), 7.77 (d, J = 9.0 Hz, 1 H), 7.34-7.25 (m, 5 H), 7.20 (d, J = 7.5Hz, 1 H), 6.68 (d, J = 9.1 Hz, 1 H), 5.19 (s, 2 H) 4.02 (s, 2 H), 2.55(s, 3 H), 1.97 (s, 3 H); MS (m/e): 391 (M + 1). 140 4-[3-(4-Acetyl-2-chloro-3-hydroxy- phenoxymethyl)- benzyl]-benzoic acid

1 H NMR (DMSO-d₆) δ 13.12 (s, 1 H) 12.83 (s, 1 H), 7.90 (d, J = 9.1 Hz,1 H), 7.84 (d, J = 8.3 Hz, 2 H), 7.35-7.27 (m, 5 H), 7.22 (d, J = 7.1Hz, 1 H), 6.85 (d, J = 9.0 Hz, 1 H), 5.29 (s, 2 H), 4.02 (s, 2 H), 2.60(s, 3 H); MS (m/e): 409 (M − 1). 141 3-[4-(4-Acetyl-3-hydroxy-2-thiophen- 3-yl-phenoxymethyl)- benzyl]-benzoic acid

1 H NMR (DMSO-d₆) δ 13.1 (bs, 1 H), 7.95 (d, J = 9.2 Hz, 1 H), 7.84-7.75(m, 2 H), 7.59-7.55 (m, 1 H), 7.53-7.48 (m, 2 H), 7.46-7.39 (m, 1 H),7.34-7.22 (m, 5 H), 6.84 (d, J = 8.8 Hz, 1 H), 5.23 (s, 2 H), 4.02 (s, 2H), 2.63 (s, 3 H); MS (m/e): 457 (M − 1).

Preparation 168 Synthesis of N-hydroxy-2-(4-methoxy-phenoxy)-acetamidine

Add sodium acetate (5.1 g, 62 mmol) to 4-methoxyphenoxyacetonitrile (5.0g, 31 mmol) and hydroxylamine hydrochloride (4.3 g, 62 mmol) in methanol(100 mL). Stir the resulting mixture at room temperature for 20 hours.Filter the resulting mixture through Celite, concentrate, stir inchloroform for 18 hours and filter. Concentrate the resulting solutionto the title compound (5.1 g). LC-MS (m/e): 197(M+1).

Preparation 169 Synthesis of4-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acidethyl ester

Add oxaxyl chloride (1.25 mL, 14 mmol) to 4-carboxymethyl-benzoic acidethyl ester (365 mg, 1.75 mmol) in benzene (11 mL) and a drop ofdimethylformamide at room temperature under argon gas over a 5 minuteperiod. Stir the reaction mixture for 2 hours at room temperature.Concentrate the reaction mixture to an oil. Redissolve the oil indimethylformamide (10 mL) andN-hydroxy-2-(4-methoxy-phenoxy)-acetamidine (380 mg, 1.9 mmol) is added.Stir the reaction mixture at room temperature for 3 hours. Heat thereaction mixture to 120° C. and stir for 7 hours. After cooling to roomtemperature, quench the reaction mixture with water and extract withethyl acetate (3×). Combine the organic layers, wash with brine, dryover sodium sulfate, and concentrate. Purify the residue by flash columnchromatography using 20% ethyl acetate/hexane to give the title compound(201 mg, 31%). LC-MS (m/e): 369(M+1).

Preparation 170 Synthesis of4-(3-hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethyl ester

Add half of the ammonium cerium(IV) nitrate (285 mg, 0.52 mmol) to asolution of4-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acidethyl ester (193 mg, 0.52 mmol) in acetonitrile (9 mL) and water (2.3mL) at room temperature. Stir the reaction mixture at room temperaturefor one hour and add the second half of the ammonium cerium(IV) nitrate(285 mg, 0.52 mmol). Stir at room temperature for an additional hour,dilute the reaction is with saturated aqueous sodium hydride CO₃, stirfor 5 minutes, dilute with water, and extract with ethyl acetate (3×).Wash the combined organic layers with brine, dry over MgSO₄, andconcentrate. Purify the residue by flash column chromatography using 50%ethyl acetate/hexane to give the title compound (720 mg, 81%). LC-MS(m/e): 263 (M+1).

Preparation 171 Synthesis of4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid ethyl ester

Add polymer support PPh₃ (287 mg, 0.86 mmol to a solution of4-(3-hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethyl ester(80 mg, 0.41 mmol) in anhydrous CH₂Cl₂ (8 mL) under argon gas at roomtemperature. Add 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (115 mg,0.62 mmol) to the mixture, followed by diisopropyl azodicarboxylate (194μL, 0.86 mmol). After 1.5 hours at room temperature, remove the polymerby filtration and concentrate the filtrate. Purify the residue by flashcolumn chromatography using 30% ethyl acetate/hexane to give the titlecompound (60 mg, 34%). LC-MS (m/e): 429 (M−1).

Example 142 Synthesis of4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid

Add 1 N hydrochloric acid (3.6 mL) to a solution of4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid ethyl ester (55 mg, 0.13 mmol) in EtOH (1.2 mL) in a microwavetube. Seal the tube and heat in a microwave reactor at 150° C. for 30min. Purify the reaction mixture by reverse phase HPLC using a gradientof 90:10 to 20:80 (H₂O/0.1% TFA):CH₃CN as eluent to give the titlecompound (17 mg, 33%). ¹H NMR (DMSO-d₆) δ 13.07 (s, 1H), 12.92 (s, 1H),7.86-7.94 (m, 3H), 7.44 (d, 2H), 6.89 (d, 1H), 5.49 (s, 2H), 4.49 (s,2H), 2.59 (s, 3H). LC-MS (m/e): 401 (M−1).

Preparation 172 Synthesis of3-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acidethyl ester

The title compound is prepared essentially as described for4-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acidethyl ester, employing 3-carboxymethyl-benzoic acid ethyl ester (45%).LC-MS (m/e): 369 (M+1).

Preparation 173 Synthesis of3-(3-hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethyl ester

The title compound is prepared essentially as described for4-(3-hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethylester, employing3-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acidethyl ester (81%). LC-MS (m/e): 263 (M+1).

Preparation 174 Synthesis of3-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid ethyl ester

The title compound is prepared essentially as described for4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid ethyl ester, employing3-(3-hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethyl ester(71%). LC-MS (m/e): 429 (M−1).

Example 143 Synthesis of3-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid

The title compound is prepared essentially as described for4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid, employing3-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid ethyl ester. ¹H NMR (DMSO-d₆) δ 13.06 (s, 1H), 12.99 (s, 1H), 7.91(m, 2H), 7.83 (m, 1H), 7.58 (m, 1H), 7.46 (dd, 1H), 6.89 (d, 1H), 5.49(s, 2H), 4.48 (s, 2H), 2.59 (s, 3H). LC-MS (m/e): 401 (M−1).

Preparation 175 Synthesis of N-hydroxy-2-(3-iodo-phenyl)-acetamidine

Add sodium carbonate (2.0 g, 18.5 mmol) to a mixture of3-iodophenylacetonitrile (4.5 g, 18.5 mmol) and hydroxylaminehydrochloride (1.3 g, 18.5 mmol) in 10:1 EtOH:H₂O (11 mL). Heat thereaction mixture to 50° C. for 2 days. Cool to RT, then filter to removethe solids. Concentrate the filtrate to afford the title compound (4.94g). LC-MS (m/e): 277 (M+1).

Preparation 176 Synthesis of5-chloromethyl-3-(3-iodo-benzyl)-[1,2,4]oxadiazole

Add a solution of chloroacetic anhydride (1.5 g, 9 mmol) in toluene (20mL) to N-hydroxy-2-(3-iodo-phenyl)-acetamidine (2.5 g, 9 mmol) inanhydrous toluene (20 mL). Fit the flask with a Dean-Stark trap and heatto reflux for 7 h. Concentrate the mixture and purify the residue byflash chromatography using 15% tetrahydrofuran/hexane to give the titlecompound (1.45 g, 48%). ¹H NMR (CDC₁₃) δ 7.65 (s, 1H), 7.59 (d, 1H),7.26 (d, 1H), 7.04 (dd, 1H), 4.62 (s, 2H), 4.01 (s, 2H).

Preparation 177 Synthesis of1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone

Add lithium carbonate (49 mg, 0.66 mmol) and5-chloromethyl-3-(3-iodo-benzyl)-[1,2,4]oxadiazole (200 mg, 0.60 mmol)to a solution of 1-(2,4-dihydroxy-3-methyl-phenyl)-ethanone (110 mg,0.66 mmol) in anhydrous dimethylformamide (20 mL) 4]oxadiazole (200 mg,0.60 mmol). Heat the reaction mixture at 60° C. overnight. Cool thereaction mixture to RT, pour into H₂O, and extract with diethyl ether(3×). Combine the organic layers, wash with brine, dry over sodiumsulfate, and concentrate to provide the title compound (150 mg). LC-MS(m/e): 463 (M−1).

Example 144 Synthesis of3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid

Combine1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone(150 mg, 0.32 mmol), sodium dodecyl sulfate (300 mg, 1.0 mmol), K₂CO₃(45 mg, 0.32 mmol), 1-butanol (200 μL), and 1 drop of toluene in H₂O (4mL) in a pressure vessel, then degas with Ar for 5 min. Add PdCl₂(MeCN)₂(18 mg, 0.07 mmol) to the reaction mixture. Exchange the atmosphere withcarbon monoxide and heat the mixture to 70° C. under 20 psi of carbonmonoxide. The reaction is heated until complete. Filter the blackmixture through filter cell. Acidify the filtrate with 5 N hydrochloricacid to pH=1. A milky white mixture forms. Add a small amount ofmethanol to induce crystallization Collect the crystals by filtration togive the title compound (79 mg, 65%). ¹H NMR (DMSO-d₆) δ 12.99 (s, 1H),12.79 (s, 1H), 7.86 (m, 1H), 7.79 (m, 2H), 7.52 (m, 1H), 7.42 (dd, 1H),6.67 (d, 1H), 5.60 (s, 2H), 4.19 (s, 2H), 2.55 (s, 3H), 1.99 (s, 3H).LC-MS (m/e): 381 (M−1).

Preparation 178 Synthesis of1-{3-chloro-2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-ethanone

The title compound is prepared essentially as described for1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone,employing 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (57%). LC-MS (m/e):483 (M−1).

Example 145 Synthesis of3-[5-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid

The title compound is prepared essentially as described for3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid of Example 140 employing1-{3-chloro-2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-ethanone.¹H NMR (DMSO-d₆) δ 13.06 (s, 1H), 12.94 (s, 1H), 7.92 (d, 1H), 7.85 (s,1H), 7.80 (m, 1H), 7.52 (m, 1H), 7.42 (dd, 1H), 6.84 (d, 1H), 5.71 (s,2H), 4.20 (s, 2H), 2.60 (s, 3H). LC-MS (m/e): 401 (M−1).

Preparation 179 Synthesis of N-hydroxy-2-(4-iodo-phenyl)-acetamidine

The title compound is prepared essentially as described forN-hydroxy-2-(3-iodo-phenyl)-acetamidine, employing(4-iodo-phenyl)-acetonitrile. LC-MS (m/e): 277 (M+1).

Preparation 180 Synthesis of5-chloromethyl-3-(4-iodo-benzyl)-[1,2,4]oxadiazole

The title compound is prepared essentially as described for5-chloromethyl-3-(3-iodo-benzyl)-[1,2,4]oxadiazole, employingN-hydroxy-2-(4-iodo-phenyl)-acetamidine. LC-MS (m/e): 335 (M+1).

Preparation 181 Synthesis of1-{3-chloro-2-hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-ethanone

The title compound is prepared essentially as described for1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone,employing 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone and5-Chlormethyl-3-(4-iodo-benzyl)-[1,2,4]oxadiazole. LC-MS (m/e): 485(M+1).

Example 146 Synthesis of4-[5-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid

The title compound is prepared essentially as described for3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid of Example 140, employing1-{3-chloro-2-hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-ethanone.¹H NMR (DMSO-d₆) δ 13.05 (s, 1H), 12.86 (s, 1H), 7.92 (d, 1H), 7.85 (m,2H), 7.38 (d, 2H), 6.84 (d, 1H), 5.72 (s, 2H), 4.18 (s, 2H), 2.59 (s,3H). LC-MS (m/e): 401 (M−1).

Preparation 182 Synthesis of1-{2-Hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone

The title compound is prepared essentially as described for1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone,employing 5-chloromethyl-3-(4-iodo-benzyl)-[1,2,4]oxadiazole and1-(2,4-Dihydroxy-3-methyl-phenyl)-ethanone. LC-MS (m/e): 463 (M−1).

Example 147 Synthesis of4-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid

The title compound is prepared essentially as described for3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid, employing1-{2-hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone.¹H NMR (DMSO-d₆) δ 12.84 (s, 1H), 12.80 (s, 1H), 7.86 (m. 2H), 7.78 (d,1H), 7.38 (d, 2H), 6.67 (d, 1H), 5.60 (s, 2H), 4.19 (s, 2H), 2.55 (s,3H), 1.99 (s, 3H). LC-MS (m/e): 381 (M−1).

Preparation 183 Synthesis of N-hydroxy-2-(4-methoxy-phenoxy)-acetamidine

Add sodium acetate (5.1 g, 62 mmol) to 4-methoxyphenoxyacetonitrile (5.0g, 31 mmol) and hydroxylamine hydrochloride (4.3 g, 62 mmol) in methanol(100 mL). Stir the resulting mixture at room temperature for 20 hours.Filter the resulting mixture through Celite, concentrate, stir inchloroform for 18 hours and filter. Concentrate the resulting solutionto the title compound (5.1 g). LC-MS (m/e): 197(M+1).

Preparation 184 Synthesis of4-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acidethyl ester

Add oxaxyl chloride (1.25 mL, 14 mmol) to 4-carboxymethyl-benzoic acidethyl ester (365 mg, 1.75 mmol) in benzene (11 mL) and a drop ofdimethylformamide at room temperature under argon gas over a 5 minuteperiod. Stir the reaction mixture for 2 hours at room temperature.Concentrate the reaction mixture to an oil. Redissolve the oil indimethylformamide (10 mL) andN-hydroxy-2-(4-methoxy-phenoxy)-acetamidine (380 mg, 1.9 mmol) is added.Stir the reaction mixture at room temperature for 3 hours. Heat thereaction mixture to 120° C. and stir for 7 hours. After cooling to roomtemperature, quench the reaction mixture with water and extract withethyl acetate (3×). Combine the organic layers, wash with brine, dryover sodium sulfate, and concentrate. Purify the residue by flash columnchromatography using 20% ethyl acetate/hexane to give the title compound(201 mg, 31%). LC-MS (m/e): 369(M+1).

Preparation 185 Synthesis of4-(3-hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethyl ester

Add half of the ammonium cerium(IV) nitrate (285 mg, 0.52 mmol) to asolution of4-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acidethyl ester (193 mg, 0.52 mmol) in acetonitrile (9 mL) and water (2.3mL) at room temperature. Stir the reaction mixture at room temperaturefor one hour and add the second half of the ammonium cerium(IV) nitrate(285 mg, 0.52 mmol). Stir at room temperature for an additional hour,dilute the reaction is with saturated aqueous sodium hydride CO₃, stirfor 5 minutes, dilute with water, and extract with ethyl acetate (3×).Wash the combined organic layers with brine, dry over MgSO₄, andconcentrate. Purify the residue by flash column chromatography using 50%ethyl acetate/hexane to give the title compound (720 mg, 81%). LC-MS(m/e): 263 (M+1).

Preparation 186 Synthesis of4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid ethyl ester

Add polymer support PPh₃ (287 mg, 0.86 mmol to a solution of4-(3-hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethyl ester(80 mg, 0.41 mmol) in anhydrous CH₂Cl₂ (8 mL) under argon gas at roomtemperature. Add 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (115 mg,0.62 mmol) to the mixture, followed by diisopropyl azodicarboxylate (194μL, 0.86 mmol). After 1.5 hours at room temperature, remove the polymerby filtration and concentrate the filtrate. Purify the residue by flashcolumn chromatography using 30% ethyl acetate/hexane to give the titlecompound (60 mg, 34%). LC-MS (m/e): 429 (M−1).

Example 148 Synthesis of4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid

Add 1 N hydrochloric acid (3.6 mL) to a solution of4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid ethyl ester (55 mg, 0.13 mmol) in EtOH (1.2 mL) in a microwavetube. Seal the tube and heat in a microwave reactor at 150° C. for 30min. Purify the reaction mixture by reverse phase HPLC using a gradientof 90:10 to 20:80 (H₂O/0.1% TFA):CH₃CN as eluent to give the titlecompound (17 mg, 33%). ¹H NMR (DMSO-d₆) δ 13.07 (s, 1H), 12.92 (s, 1H),7.86-7.94 (m, 3H), 7.44 (d, 2H), 6.89 (d, 1H), 5.49 (s, 2H), 4.49 (s,2H), 2.59 (s, 3H). LC-MS (m/e): 401 (M−1).

Preparation 187 Synthesis of3-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acidethyl ester

The title compound is prepared essentially as described for4-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acidethyl ester, employing 3-carboxymethyl-benzoic acid ethyl ester (45%).LC-MS (m/e): 369 (M+1).

Preparation 188 Synthesis of3-(3-hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethyl ester

The title compound is prepared essentially as described for4-(3-hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethylester, employing3-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acidethyl ester (81%). LC-MS (m/e): 263 (M+1).

Preparation 189 Synthesis of3-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid ethyl ester

The title compound is prepared essentially as described for4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid ethyl ester, employing3-(3-Hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethyl ester(71%). LC-MS (m/e): 429 (M−1).

Example 149 Synthesis of3-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid

The title compound is prepared essentially as described for4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid, employing3-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoicacid ethyl ester. ¹H NMR (DMSO-d₆) δ 13.06 (s, 1H), 12.99 (s, 1H), 7.91(m, 2H), 7.83 (m, 1H), 7.58 (m, 1H), 7.46 (dd, 1H), 6.89 (d, 1H), 5.49(s, 2H), 4.48 (s, 2H), 2.59 (s, 3H). LC-MS (m/e): 401 (M−1).

Preparation 190 Synthesis of N-hydroxy-2-(3-iodo-phenyl)-acetamidine

Add sodium carbonate (2.0 g, 18.5 mmol) to a mixture of3-iodophenylacetonitrile (4.5 g, 18.5 mmol) and hydroxylaminehydrochloride (1.3 g, 18.5 mmol) in 10:1 EtOH:H₂O (11 mL) Heat thereaction mixture to 50° C. for 2 days. Cool to RT, then filter to removethe solids. Concentrate the filtrate to afford the title compound (4.94g). LC-MS (m/e): 277 (M+1).

Preparation 191 Synthesis of5-chloromethyl-3-(3-iodo-benzyl)-[1,2,4]oxadiazole

Add a solution of chloroacetic anhydride (1.5 g, 9 mmol) in toluene (20mL) to N-hydroxy-2-(3-iodo-phenyl)-acetamidine (2.5 g, 9 mmol) inanhydrous toluene (20 mL). Fit the flask with a Dean-Stark trap and heatto reflux for 7 h. Concentrate the mixture and purify the residue byflash chromatography using 15% tetrahydrofuran/hexane to give the titlecompound (1.45 g, 48%). ¹H NMR (CDC₁₃) δ 7.65 (s, 1H), 7.59 (d, 1H),7.26 (d, 1H), 7.04 (dd, 1H), 4.62 (s, 2H), 4.01 (s, 2H).

Preparation 192 Synthesis of1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone

Add lithium carbonate (49 mg, 0.66 mmol) and5-chloromethyl-3-(3-iodo-benzyl)-[1,2,4]oxadiazole (200 mg, 0.60 mmol)to a solution of 1-(2,4-dihydroxy-3-methyl-phenyl)-ethanone (110 mg,0.66 mmol) in anhydrous dimethylformamide (20 mL) 4]oxadiazole (200 mg,0.60 mmol). Heat the reaction mixture at 60° C. overnight. Cool thereaction mixture to RT, pour into H₂O, and extract with diethyl ether(3×). Combine the organic layers, wash with brine, dry over sodiumsulfate, and concentrate to provide the title compound (150 mg). LC-MS(m/e): 463 (M−1).

Example 150 Synthesis of3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid

Combine1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone(150 mg, 0.32 mmol), sodium dodecyl sulfate (300 mg, 1.0 mmol), K₂CO₃(45 mg, 0.32 mmol), 1-butanol (200 μL), and 1 drop of toluene in H₂O (4mL) in a pressure vessel, then degas with Ar for 5 min. Add PdCl₂(MeCN)₂(18 mg, 0.07 mmol) to the reaction mixture. Exchange the atmosphere withcarbon monoxide and heat the mixture to 70° C. under 20 psig of carbonmonoxide. The reaction is heated until complete. Filter the blackmixture through celite. Acidify the filtrate with 5 N hydrochloric acidto pH=1. A milky white mixture forms. Add a small amount of methanol toinduce crystallization Collect the crystals by filtration to give thetitle compound (79 mg, 65%). ¹H NMR (DMSO-d₆) δ 12.99 (s, 1H), 12.79 (s,1H), 7.86 (m, 1H), 7.79 (m, 2H), 7.52 (m, 1H), 7.42 (dd, 1H), 6.67 (d,1H), 5.60 (s, 2H), 4.19 (s, 2H), 2.55 (s, 3H), 1.99 (s, 3H). LC-MS(m/e): 381 (M−1).

Preparation 193 Synthesis of1-{3-chloro-2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-ethanone

The title compound is prepared essentially as described for1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone,employing 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (57%). LC-MS (m/e):483 (M−1).

Example 151 Synthesis of3-[5-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid

The title compound is prepared essentially as described for3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid of Example 146 employing1-{3-chloro-2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-ethanone.¹H NMR (DMSO-d₆) δ 13.06 (s, 1H), 12.94 (s, 1H), 7.92 (d, 1H), 7.85 (s,1H), 7.80 (m, 1H), 7.52 (m, 1H), 7.42 (dd, 1H), 6.84 (d, 1H), 5.71 (s,2H), 4.20 (s, 2H), 2.60 (s, 3H). LC-MS (m/e): 401 (M−1).

Preparation 194 Synthesis of N-hydroxy-2-(4-iodo-phenyl)-acetamidine

The title compound is prepared essentially as described forN-hydroxy-2-(3-iodo-phenyl)-acetamidine, employing(4-iodo-phenyl)-acetonitrile. LC-MS (m/e): 277 (M+1).

Preparation 195 Synthesis of5-chloromethyl-3-(4-iodo-benzyl)-[1,2,4]oxadiazole

The title compound is prepared essentially as described for5-chloromethyl-3-(3-iodo-benzyl)-[1,2,4]oxadiazole, employingN-hydroxy-2-(4-iodo-phenyl)-acetamidine. LC-MS (m/e): 335 (M+1).

Preparation 196 Synthesis of1-{3-chloro-2-hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-ethanone

The title compound is prepared essentially as described for1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone,employing 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone and5-Chlormethyl-3-(4-iodo-benzyl)-[1,2,4]oxadiazole. LC-MS (m/e): 485(M+1).

Example 152 Synthesis of4-[5-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid

The title compound is prepared essentially as described for3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid of Example 146, employing1-{3-chloro-2-hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-ethanone.¹H NMR (DMSO-d₆) δ 13.05 (s, 1H), 12.86 (s, 1H), 7.92 (d, 1H), 7.85 (m,2H), 7.38 (d, 2H), 6.84 (d, 1H), 5.72 (s, 2H), 4.18 (s, 2H), 2.59 (s,3H). LC-MS (m/e): 401 (M−1).

Preparation 197 Synthesis of1-{2-hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone

The title compound is prepared essentially as described for1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone,employing 5-chloromethyl-3-(4-iodo-benzyl)-[1,2,4]oxadiazole and1-(2,4-Dihydroxy-3-methyl-phenyl)-ethanone. LC-MS (m/e): 463 (M−1).

Example 153 Synthesis of4-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid

The title compound is prepared essentially as described for3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoicacid of Example 146, employing1-{2-hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone.¹H NMR (DMSO-d₆) δ 12.84 (s, 1H), 12.80 (s, 1H), 7.86 (m. 2H), 7.78 (d,1H), 7.38 (d, 2H), 6.67 (d, 1H), 5.60 (s, 2H), 4.19 (s, 2H), 2.55 (s,3H), 1.99 (s, 3H). LC-MS (m/e): 381 (M−1).

Preparation 198 Synthesis of 5-(3-bromophenyl)isoxazol-3-ol

Add a solution of hydroxyamine (50% in water, 0.50 mL, 16.3 mmol) inwater and NaOH (197 mg, 4.92 mmol) to a solution of methyl3-(3-bromophenyl)propiolate (980 mg, 4.10 mmol) in a mixture of MeOH andTHF (6.0 mL/12.0 mL). Remove the solvents after 2 d. Dissolve theresidue in water. Adjust the pH of the aqueous phase to 2 and extractwith EtOAc. Dry, filter and concentrate. Purify the residue by flashchromatography eluting with a mixture of EtOAc and hexanes (50:50) toafford the title compound (856 mg, 87%): ¹H NMR (d₆-DMSO) δ 11.54 (s,1H), 8.08 (dd, 1H, J=2.0, 1.6 Hz), 7.87 (ddd, 1H, J=8.6, 1.6, 0.8 Hz),7.75 (ddd, 1H, J=8.2, 2.0, 0.8 Hz), 7.54 (t, 1H, J=7.8 Hz), 6.75 (s,1H).

Preparation 199 Synthesis of 3-(3-hydroxyisoxazol-5-yl)phenylboronicacid

Add a 2.5 M solution of n-butyllithium in hexane (0.60 mL, 1.10 mmol) toa solution of 5-(3-bromophenyl)isoxazol-3-ol (120 mg, 0.50 mmol) andtriisopropyl borate (113 mg, 0.60 mmol) in a mixture of toluene (2.5 mL)and THF (2.5 mL) at −78° C. After 1.5 h, warm the mixture to −20° C. andadd a 2.0 N aqueous HCl solution (1 mL). Extract the mixture with EtOAcafter warm to room temperature. Dry, filter and concentrate the organiclayer to a white solid.

Preparation 200 Synthesis of1-(4-(4-(bromomethyl)benzyloxy)-3-chloro-2-hydroxyphenyl)ethanone

Add K₂CO₃ (1.48 g, 10.7 mmol) to a solution of1-(3-chloro-2,4-dihydroxy-phenyl)ethanone (2.00 g, 10.7 mmol) and1,4-bis(bromomethyl)benzene (2.83 g, 10.7 mmol) in acetone (100 mL).Cool and work up with a 10% HCl solution and EtOAc. Triturate in acetoneto remove insoluble material. Dry, filter, and concentrate. Purify theresidue by flash chromatography on silica gel (731 mg, 18%): MS (esinegative) m/z 368.9 (rel intensity) (M−H, 55%), 367.0 (45%).

Example 154 Synthesis of1-(4-(4-(3-(3-Hydroxyisoxazol-5-yl)benzyl)benzyloxy)-3-chloro-2-hydroxyphenyl)ethanone

Add 1-(4-(4-(bromomethyl)benzyloxy)-3-chloro-2-hydroxyphenyl)ethanone(180 mg, 0.487 mmol) and 3-(3-hydroxyisoxazol-5-yl)phenylboronic acid(218 mg, 1.06 mmol) to a 2.0 M solution of Na₂CO₃ in water (2.36 mL),dimethoxyethane (4.72 mL), and n-PrOH (4.72 mL). Degas the solution. Addtetrakis(triphenylphosphine)palladium (0) (123 mg, 0.106 mmol) and degasthe mixture. Heat the mixture at 70° C. for 12 h. Quench the reactionwith water. Extract with EtOAc. Dry, filter and concentrate. Purify theresidue by flash chromatography on silica gel afforded the titlecompound (12 mg, 5%): ¹H NMR (d₆-DMSO) δ 2.61 (s, 3H), 4.02 (s, 2H),5.31 (s, 2H), 6.51 (s, 1H), 6.89 (d, J=9.0 Hz, 1H), 7.31-7.36 (m, 3H),7.39-7.44 (m, 3H), 7.62 (d, J=7.8 Hz, 1H), 7.70 (s, 1H), 7.93 (d, J=9.4Hz, 1H), 11.34 (s, 1H), 13.13 (s, 1H); MS (APCI-neg mode) m/z (relintensity): 448 (M−H, 100%).

Preparation 201 Synthesis of2,4,6-Tris-[4-(tert-butyldimethylsilanyloxymethyl)-phenyl]-cyclotriboroxane

Combine (4-bromobenzyloxy)-tert-butyldimethylsilane (390.0 g, 1.29 mol),THF (3.90 L), toluene (827 mL) and triisopropyl borate (353.0 g, 1.88mol) in a 12 L round-bottom flask at RT. Stir for 30 min. Cool thesolution to −78° C. Add n-hexyllithium while maintaining the solutiontemperature <−68° C. Warm to −20° C. Add the reaction mixture to 2 N HCl(1325 mL). Warm the mixture to 0° C., and stir for 30 min. Add ethylacetate (2.1 L) and stir the resulting mixture at 0° C. for 30 min.Separate the layers and wash the organic layer with 2 L of 5% aqueousNaHCO₃ containing NaCl (90 g). Concentrate the organic layer in vacuo toapproximately 3 L total volume. Add acetonitrile (3 L) and concentratein vacuo to 3 L total volumes. Repeat this process three times. Addacetonitrile (3 L) and stir overnight at RT. Cool the slurry to 0° C.,stir for 30 min and filter. Wash the filter cake with acetonitrile (500mL). Dry the resulting off-white solid under vacuum at 45° C. to affordthe title compound: ¹H NMR (500 MHz, CDC₁₃) δ 8.22 (d, J=8.2 Hz, 6H),7.47 (d, J=8.2 Hz, 6H), 4.85 (s, 6H), 0.98 (s, 27H), 0.14 (s, 18H).

Preparation 202 Synthesis of3-{[4-(tert-butyldimethylsilanyloxymethyl)phenyl]-(S)-hydroxymethyl}-benzonitrile

Under a nitrogen purge, add 1.1M diethyl zinc in toluene (312.3 mL,343.5 mmol) to2,4,6-Tris-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-cylcotriboroxane(30.1 g, 40.4 mmol) at ambient temperature and stir. After 5 minutes,heat to 60° C. and stir overnight. Cool to −10° C. and add via syringe,a mixture of (R)-(−)-2-Piperidino-1,1,2-triphenylethanol (6.7 g, 18.7mmol) in toluene (70 mL) and stir 30 minutes. Via syringe, add a mixtureof 3-cyanobenzaldehyde (12.2 g, 93.3 mmol) in toluene (40 mL) andcontinue stirring at −10 to −5° C. After 4 hours, add a mixture ofacetic acid (59.0 mL, 1030 mmol) and deionized water (14 mL) to themixture over 20 minutes. Filter off the resulting solids and rinse withtoluene (50 mL). Wash the filtrate sequentially with 0.5 N HCl (2×200mL), water (2×100 mL), 0.5N NaOH (200 mL), and water (100 mL). Dry theorganic layer over sodium sulfate, filter, and concentrate under reducedpressure to give a crude residue. Purify the residue by dissolving inacetonitrile (330 mL) and performing heptane extractions (1×66 mL, 5×33mL). Concentrate the acetonitrile portion under reduced pressure to givethe title compound as a clear, thick oil: ¹H NMR (500 MHz, CDC₁₃) δ 0.04(s, 6H), 0.87 (s, 9H), 4.64 (s, 2H), 5.74 (d, 1H), 6.08 (d, 1H), 7.22(d, 2H, J=8.3 Hz), 7.33 (d, 2H, J=8.3 Hz), 7.49 (t, 1H), 7.64-7.68 (m,2H), 7.78 (s, 1H). HPLC retention time: 6.3 minutes; Zorbax SB-C8 RapidResolution 4.6×75 mm 3.5-micron column. 220 nm wavelength, columntemperature 30° C., 2 mL/min flow rate, A=0.1% H₃PO₄/milli-q water,B=Acetonitrile, Time=0 minute, 80% A, Time=0.5 minutes, 80% A, Time=7minutes, 10% A, Time=8 minutes 10% A, Time=8.5 minutes 80% A, Time=9minutes 80% A. Chiral assay retention time: desired isomer 7.1 minutes;95.5% ee; ChiralCell AD-H 46×150 mm column, 240 nm wavelength, ambientcolumn temperature, 0.8 mL/min flow rate. Eluent=1% 3A-Ethanol, 4%Methanol, 95% Heptane (v/v), isocratic run time=15 minutes.

Preparation 203 Synthesis of3-[4-(hydroxymethylphenyl)-(S)-acetoxymethyl]-benzonitrile

To a flask add acetic acid acetic acid anhydride (10.64 g, 104.20 mmol),triethylamine (11.37 g, 112.35 mmol), and N,N-dimethyl-4-pyridinamine(226.00 mg, 1.85 mmol) to3-{[4-(tert-butyldimethylsilanyloxymethyl)phenyl]-(S)-hydroxymethyl}-benzonitrile(28.35 g, 80.19 mmol) in a solution of acetonitrile and heptane (280 mL)under nitrogen atmosphere and stir for 1 hour at ambient temperature toafford acetic acid3-[4-(tert-butyl-dimethyl-silanyloxymethylphenyl)-(S)-acetoxymethyl]-benzonitrile.To this reaction solution add 5 N HCl (28 mL, 140 mmol) and stir for2.75 hours at ambient temperature. Wash the reaction solution withheptane (3×320 mL) and transfer to a separatory funnel. Add toluene (476mL) and deionized water (320 mL), agitate and separate the layers.Extract the aqueous layer with toluene (320 mL) and combine the organiclayers. Wash the combined organics with saturated NaHCO₃ solution (320mL), water (320 mL), concentrate to 40 mL total volume by vacuumdistillation. Add toluene (286 mL) to afford a solution of the titlecompound. This solution may be taken into the proceeding step withoutpurification. HPLC retention time: 3.69 minutes; Zorbax SB-C8 RapidResolution 4.6×75 mm 3.5-micron column. 220 nm wavelength, columntemperature 30° C., 2 mL/min flow rate, A=0.1% H₃PO₄/milli-q water,B=Acetonitrile, Time=0 minute, 80% A, Time=0.5 minutes, 80% A, Time=7minutes, 10% A, Time=8 minutes 10% A, Time=8.5 minutes 80% A, Time=9minutes 80% A.

Preparation 204 Synthesis of3-[4-(methanesulfonyloxymethylphenyl)-(S)-acetoxymethyl]-benzonitrile

Add triethylamine (8.94 g, 88.39 mmol) to a solution of3-[4-(hydroxymethylphenyl)-(S)-acetoxymethyl]-benzonitrile (20.70 g,73.58 mmol) in toluene (˜310 mL) at −2° C. under nitrogen atmosphere.Add methanesulfonyl chloride (9.69 g, 84.63 mmol) over a period of 30minutes and stir for 1 hour at 0° C. Wash the reaction solution withwater (2×210 mL), concentrate in vacuo to 75 mL total to afford asolution of the title compound, and take directly into the proceedingstep: HPLC retention time: 4.52 minutes; Zorbax SB-C8 Rapid Resolution4.6×75 mm 3.5-micron column. 220 nm wavelength, column temperature 30°C., 2 mL/min flow rate, A=0.1% H₃PO₄/milli-q water, B=Acetonitrile,Time=0 minute, 80% A, Time=0.5 minutes, 80% A, Time=7 minutes, 10% A,Time=8 minutes 10% A, Time=8.5 minutes 80% A, Time=9 minutes 80% A.

Preparation 205 Synthesis of3-{[4-(4-acetyl-3-hydroxy-2-propylphenoxymethyl)-phenyl]-(S)-acetoxymethyl}-benzonitrile

Add3-[4-(methanesulfonyloxymethylphenyl)-(S)-acetoxymethyl]-benzonitrile(26.45 g, 73.59 mmol) in toluene (˜53 mL) to a flask containing acetone(344 mL), 2′,4′-dihydroxy-3′-propyl-acetophenone (12.91 g, 66.47 mmol),and K₂CO₃ (10.21 g, 73.88 mmol) and stir under a nitrogen atmosphere.Heat to 60° C. for 6.5 hours. Add 2′,4′-dihydroxy-3′-propyl-acetophenone(670 mg, 3.44 mmol) and stir the suspension for 5.5 h. Cool the reactionto ambient temperature and filter. Wash the filter cake with toluene (3vol) and concentrate in vacuo to 132 mL. Wash the concentrate withdeionized water (2×132 mL) and further concentrate in vacuo to 60 mL.Add hot absolute EtOH (240 mL) and concentrate in vacuo to 234 mL. Addhot EtOH (66 mL) to the solution and concentrate to 100 mL. To the hotsolution, add absolute EtOH (190 mL), stir, and slowly cool to ambienttemperature. Stir the suspension for 15 hours and filter. Wash thefilter cake with absolute EtOH (34 mL) and dry the resulting solid in avacuum oven at 45° C. Add dry, crystalline3-{[4-(4-acetyl-3-hydroxy-2-propylphenoxymethyl)-phenyl]-(S)-acetoxymethyl}-benzonitrile(24.54 g) and MTBE (123 mL) to a flask and heat to reflux for 10minutes. Cool the resulting solution to 27° C. before adding heptane (50mL) dropwise over 20 minutes. Stir the mixture at ambient temperaturefor two hours and filter. Wash the filter cake and flask with 50/50MTBE/heptane and dry in a vacuum oven at 45° C. to afford the titlecompound: mass spectrum (m/e): 456.5 (M−); ¹H NMR (500 MHz, DMSO) δ12.82(s, 1H), 7.91 (s, 1H), 7.55 (t, 1H, 7 Hz), 7.45 (d, 2H, J=8 Hz), 7.42(d, 2H, J=8 Hz), 6.83 (s, 1H), 6.68 (d, 1H, J=8 Hz), 5.21 (s, 2H),2.55-2.58 (m, 2H), 2.54 (s, 3H), 2.15 (s, 3H), 1.42-1.49 (m, 2H), 0.84(t, 3H, J=7 Hz), ppm.

Example 155 Synthesis of3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(S)-hydroxymethyl}-benzoicacid

To a flask under nitrogen atmosphere add3-{[4-(4-acetyl-3-hydroxy-2-propylphenoxy-methyl)-phenyl]-(S)-acetoxymethyl}-benzonitrile(19.40 g, 42.40 mmol) and DI water (390 mL). Heat the suspension to 60°C. and stir for 30 minutes. Add KOH (16.86 g, 255.32 mmol) and heat theflask to 101° C. for 22.5 hours. Cool the solution to 36° C. and acidifywith 5N HCl (59.4 mL, 296.8 mmol) over 30. Cool the mixture to 25° C.over 1 hour and filter. Wash the cake and flask with deionized water(3×100 mL). Place the filter cake in a vacuum oven at 45° C. for 24hours. Add the dry solid to a flask with absolute EtOH (278 mL) and stirat reflux for 30 min. Cool the suspension to room temperature and adddeionized water (278 mL) dropwise over 25 minutes. Stir the suspensionfor 1 hour at room temperature and filter. Wash the flask and cake with50% aqueous EtOH (20 mL) and dry in a vacuum oven at 45° C. overnight toafford the title compound. mass spectrum (m/e): 433.5 (M−); ¹H NMR (500MHz, DMSO) δ 0.84 (t, 3H, J=7 Hz), 1.45 (q, 2H, J=7 Hz), 2.54 (s, 3H),2.49-2.57 (m, 2H), 5.19 (s, 2H), 5.77 (d, 1H), 6.02 (d, 1H), 6.67 (d,1H), 7.36-7.43 (m, 5H), 7.61 (d, 1H), 7.77 (dd, 2H), 7.95 (s, 1H), 12.82(s, 1H), 12.90 (s, 1H) ppm; melting point (DSC onset)=198.35° C.

1. A compound of formula I

wherein R¹ is selected from the group consisting of C1-C5 alkyl, C3-C7cycloalkyl, C4-C8 cycloalkylalkyl, phenyl and substituted phenyl; R² isselected from the group consisting of hydrogen, C1-C5 alkyl, substitutedC1-C5 alkyl, halo, phenyl, substituted phenyl, C1-C3 fluoroalkyl, CN,CO₂R³, thiophenyl, substituted thiophenyl, thiazolyl, substitutedthiazoyl, furanyl, substituted furanyl, pyridinyl, substitutedpyridinyl, oxazolyl, substituted oxazloyl, isothiazolyl, substitutedisothiazoyl, isoxazolyl, substituted isoxazolyl, 1,2,4-oxadiazolyl,substituted 1,2,4-oxadiazolyl, pyrimidinyl, substituted pyrimidinyl,pyridazinyl, and substituted pyridazinyl; X is selected from the groupconsisting of O, S(O)_(m), and NR³; Y is selected from the groupconsisting of C1-C3 alkanediyl and substituted C1-C3 alkanediyl; Ar₁ is1,2,4-oxadiazole-3,5-diyl; Ar₂ is phenylene or substituted phenylene; Lis selected from the group consisting of C1-C5 alkanediyl, substitutedC1-C5 alkanediyl, and -G-C(═W)-J-; W is CR³R³, O or NR³; G and J areindependently selected from the group consisting of a bond and C 1-C3alkanediyl; R³ is independently hydrogen or C1-C5 alkyl; Z is selectedfrom the group consisting of (CH₂)_(n)COOH,

m is Q, 1, or 2; n and q are independently 0, 1, 2 or 3; andpharmaceutically acceptable salts thereof.
 2. A compound according toclaim 1 wherein Z is selected from the group consisting of(CH₂)_(n)COOH,


3. A compound according to claim 2 wherein X is O.
 4. A compoundaccording to claim 3 wherein Y is C1-C3 alkanediyl.
 5. A compoundaccording to claim 4 wherein R² is selected from the group consisting ofC1-C5 alkyl, halo and C1-C3 fluoroalkyl.
 6. A compound according toclaim 5 wherein L is selected from the group consisting of —(CH₂)—,—CH(OH)—, and C(═O).
 7. A compound according to claim 1 wherein Z isselected from the group consisting of (CH₂)_(n)COOH and

and n and q are
 0. 8. A compound according to claim 1 wherein Ar₂ isattached at the 1-4 position.
 9. A compound according to claim 1 whereinAr₂ is attached at the 1-3 position.
 10. A compound according to claim 7wherein R¹ is methyl.
 11. A compound according to claim 1 wherein R¹ ismethyl or ethyl; R² is selected from the group consisting of methyl,ethyl, n-propyl, iso-propyl, fluoro, chloro, iodo, phenyl,4-fluorophenyl, trifluoromethyl, CN, 2-thiophenyl, 3-thiophenyl,2-thiazolyl, 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl; X is selectedfrom the group consisting of O, S, SO₂, NH and NCH₃; Y is methylene; Ar₁is 1,2,4-oxadiazole-3,5-diyl; Ar₂ is selected from the group consistingof phenylene, fluorophenylene and methoxyphenylene; L is selected fromthe group consisting of CH₂, CHCH₃, CH(OH), CH(F), CHN₃, CH(OCH₃),CHNH₂, CHNH(C═O)CH₃, CHNH(SO₂)CH₃, C═O, and CH═CH₂; Z is selected fromthe group consisting of (CH₂)_(n)COOH,

n is 0; and q is
 0. 12. A pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically acceptable carrier, diluentor excipient.
 13. A method of treating migraine, comprisingadministering to a patient in need thereof an effective amount of acompound of claim
 1. 14. A process for preparing the compound of formulaI, or a pharmaceutically acceptable salt thereof, wherein R¹, R², X, Y,Ar₁, L and Ar₂ are defined as in claim 1 comprising the step selectedfrom (A) for a compound of formula I where Z is tetrazolyl,

cycloaddition of a compound of formula II where R¹⁰ is cyano with anazide reagent;

(B) for a compound of formula I where Z is COOH,

hydrolysis of a compound of formula II wherein R¹⁰ is COOR¹⁴ and R¹⁴ isselected from the group consisting of C1-C5 alkyl, phenyl and benzyl;

(C) for a compound of formula I where Z is COOH,

hydrolysis of a compound of formula II where R¹⁰ is cyano; and

(D) for a compound of formula I

where Z is

cyclocondensating a compound of formula II where R¹⁰ is an acyl halidesuch as the acyl chloride;

whereafter, when a pharmaceutically acceptable salt of the compound offormula I is required, it is obtained by reacting the acid of formula Iwith a physiologically acceptable base or by reacting a basic compoundof formula I with a physiologically acceptable acid.
 15. A compound offormula II

wherein R¹, R², X, Y, Ar₁, Ar₂ and L are defined as in claim 1; and R¹⁰is CN or COOR¹⁴ in which R¹⁴ is selected from the group consisting ofC1-C5 alkyl, phenyl and benzyl.
 16. The compound according to claim 15wherein R¹⁴ is C1-C5 alkyl.